Autobiography of William L. Jorgensen: Scientific History and

Special Issue Preface pubs.acs.org/JPCB

Autobiography of William L. Jorgensen: Scientific History and Recollections

D

significantly with Allen and Paul Schleyer as he moved into the ab initio realm. As the Allen group was curious about the SMO methods, graduate student Bob Davidson and I obtained Pople’s CNDO program (a few hundred punch cards) from the Quantum Chemistry Program Exchange. To run the SMO program, one read the deck of cards for the code followed by the cards containing the Cartesian coordinates of a molecule into a card reader for Princeton’s IBM 7094 or 360. These were single-points, no automatic geometry optimization back then. The result was my first publication, a JACS paper in 1970 evaluating CNDO and NDDO results for organic molecules;1 there were two more publications with Allen analyzing charge density changes for rotational barriers using a program that I wrote to make electron density or MO 2-D contour plots on a CalComp plotter. Peter Kollman was also present as a graduate student with Lee Allen. Peter and Lee were always so positive and enthusiastic that I figured chemistry must be a great field. Though I had learned BASIC on my own, in the fall of 1967, Peter taught me FORTRAN in blackboard sessions in the basement of the Frick Lab. Thus, began a life-long friendship; we evolved in parallel scientifically and shared the advances at each step. Though Peter and Lee did seminal ab initio studies of hydrogen-bonded complexes, they ended up on the wrong side of the polywater controversy using the CNDO program. John Deutch, with whom I have had a warm but too infrequent relationship, was an Assistant Professor at Princeton then and expressed his disbelief in polywater. John left shortly for MIT, and Peter went off to postdoc with David Buckingham at Cambridge. Subsequently, in the early 1970s difficult job market, Peter accepted a junior faculty position in a newly forming department at UCSF that also contained former Princeton faculty members Irwin “Tack” Kuntz and Bob Langridge. Together they made great advances in macromolecular modeling and visualization. A few final notes on the Princeton period, 1967−1970: I stayed in Princeton for the summers of 1969 and 1970 working in the Allen group. For the first summer (1968), I lived with my brother and worked for IBM in Bethlehem, PA writing software for businesses that were just converting their manual billing systems to computers. The background formed by the Vietnam War, the military draft and lottery, the music and psychedelic revolutions, and student strikes in the spring of 1970 made for a less than optimal college experience. I survived, though many of my classmates tuned in, turned on, and dropped out, including three of my five suite-mates from 1968. At graduation in 1970, there were the first women to receive a Bachelor’s degree, and Bob Dylan received an honorary degree. He wrote “Day of the Locusts” about the event“I put down my robe, picked up my diploma...Sure was glad to get out of there alive.”

id I have a Gilbert Chemistry Set and always want to be a chemist? Yes, my parents gave me the chemistry set in the early 1960s. In those days, you could get many chemicals at local drug or hardware storesno questions, just smiles for the adventurous kid. Potassium nitrate was a favorite. No, I wandered into being a chemist. Many things interest me, and I think that I could have had numerous alternative careers. However, to excel at a discipline, I did recognize that one must truly focus on it. My professional future began to emerge in high school; I went to Phillips Exeter Academy in Exeter, NH. It was a rigorous place with many smart students, where one ate, slept, studied, went to class, and did sports. With a B average in my senior year, I was in the top 10% of the class (high honors)no grade inflation there. Math and science provided the greatest resonance, though I did enjoy reading Virgil (“Arma virumque cano...”) and even Dostoyevsky (“On an exceptionally hot evening...”). For the senior year, AP chemistry or physics were options; I picked chemistry because molecules were more fun than springs and because the teacher, Charles L. “Doc” Bickel, had literally written the book. The next stop was Princeton, which was appealing because it had a good engineering program. I thought that I might major in chemical engineering for the briefly considered pairing of the AP chemistry and the fact that my only sibling, Lane, had graduated from Lehigh as an engineer.

■

PRINCETON (1967−1970) Arriving at Princeton, I found that because of my AP credits I could graduate in three years. This set well with my father in view of the savings of $3000; yes, I received a Princeton Bachelor’s degree for less than $10,000. So, I started in the ChemE sequence and had to choose between physical and organic chemistry in the first semester. I picked physical, and the professor, Walter J. Kauzmann, can largely be held responsible for my being a chemist. He was an inspiring teacher, scholar, and presence and had written the three books that we used on Kinetics, Thermodynamics, and “Quantum Mechanics in Chemistry”. In year two, my organic professors, Paul von Ragué Schleyer and Ted Taylor, were excellent, too. Paul had an exotic image among the undergraduates; rumors were that he was descended from Prussian royalty. Fortunately, there was no Wikipedia to burst the bubble; Paul grew up in Cleveland. Neil Bartlett for inorganic was fine; the highlight there was my lab TA, Joan Valentine. Princeton is terrific at getting undergraduates into research. After changing my major to Chemistry in the first semester, I soon became affiliated with the research group of Leland C. Allen. Allen was among the earliest people doing ab initio quantum mechanics. His program was called Mole; other key packages were associated with IBM (Clementi), NYU (Moskowitz), Ohio State (Shavitt, Pitzer), MIT (Slater), and Harvard (Lipscomb). There was no Gaussian. In fact, John Pople was developing semiempirical MO methods (CNDO, INDO, NDDO) at that time and subsequently interacted © 2015 American Chemical Society

Special Issue: William L. Jorgensen Festschrift Published: January 22, 2015 624

dx.doi.org/10.1021/jp510442j | J. Phys. Chem. B 2015, 119, 624−632

The Journal of Physical Chemistry B

■

Special Issue Preface

HARVARD (1970−1975) Lee Allen thought that I should go to Harvard to work with Martin Karplus. Being 1970, the other contender, Berkeley, was viewed by my parents as poised for divine retribution. When I arrived at Harvard, I learned that Karplus was about to take a leave to be a faculty member in Paris and the date of his return was at best uncertain. The job market for physical chemists was also very poor, with many looking for alternate careers, so broadening my horizons seemed advisible. Luckily, Dave Pensak (Princeton ’69) had preceded me to Harvard and was working in E. J. Corey’s group as a graduate student on the retrosynthetic analysis program OCSS that became LHASA. Dave nudged me toward Corey, who seemed happy to add me owing to my programming skills. Corey was also kind in understanding that my chemical physics major would cause me to engage in some additional activities. OCSS was originally developed on a DEC PDP-1computer in the venerable Aiken Computation Lab. I worked a little on the PDP-1, all in assembly language, and then switched to the development of LHASA on the new PDP-10, which had a FORTRAN compiler. The PDP-1 had the first graphics terminals that I ever saw, big round CRTs with a Rand stylus and tablet that allowed Corey’s postdoc Todd Wipke to write the first interactive software for the input and manipulation of chemical structures.2 Jeff Howe, the first graduate student on the project, did wonders on the PDP-1 and went on to create pioneering software for compound registry and de novo design at Upjohn. Dave Pensak (later DuPont) and I, the second and third graduate students, worked on the chemistry modules for LHASA to allow one-group (e.g., Grignard disconnection), two-group (e.g., aldol), functional group addition (e.g., Wolff−Kishner), and functional group interchange (e.g., carbonyl reduction) processes. I also wrote code for recognition of identical appendages, R/S designations, symmetry, and for strategies like reconnections of chains into rings or large rings into fused rings (e.g., retro-Grob). Two JACS publications resulted. I would often write code in long concentrated sessions, uninterrupted by social media. There were computer terminals with screens, but no remote access, so all work was done in the Aiken Lab. It was a busy place at all hours. The computer science people, including Bill Gates during 1973− 1975, were the dominant presence. Among Corey’s people there was also Dick Cramer (subsequently SKF and Tripos) and George Petersson; George wrote the code for ring perception before starting his career in fundamental quantum mechanics at Wesleyan. The work for Corey introduced me to what became “cheminformatics”, including structure representation, feature perception, and set operations. I learned to anticipate problems and unexpected use of code. Thanks to Corey, I also developed a solid knowledge and appreciation of synthetic organic chemistry. I have always had the greatest admiration for Corey and his accomplishments. The diverse activities under his guidance from organic synthesis and reaction discovery to computer science were extraordinary. Meanwhile, I maintained my QM interests. I had brought the Pople CNDO code and my 2-D orbital plotting program from Princeton. Following the MINDO developments of Dewar, which seemed exciting, I modified the CNDO code to implement and test the succession of MINDO versions. I had also morphed it into an extended Hückel theory (EHT) program by adding the overlap matrix and nonorthogonal eigenvalue routines. Additionally, I devised a revised CNDO

method (RCNDO) that performed as well as MINDO/2 without the added integrals but never published it. Thus began my activities at parameter optimization. At this time, I was also interacting with Assistant Professor Weston T. Borden, who wanted someone to do QM calculations to address issues of unusual reactivity and spectra caused by orbital strain in molecules like bicyclo[2.1.1]hex-2-ene. Overlap repulsion was an issue so the EHT program was needed. This led to several publications and close friendship. In addition, I took advantage of meeting visiting professors, especially Jean-Marie Lehn (Strasbourg) and Lionel Salem (CNRS − Orsay), then in their early thirties. I showed Lionel some of my 2-D orbital plots, and he thought it would be great if I could do them in 3-D. That is, so far, they had been contour plots in one geometric plane, but with multiple contour levels, i.e., a topographic map. For 3-D there would be one contour level and I would have to compute many maps for slices in two sets of orthogonal planes. So, I wrote the code, which included having to solve the “hidden-line elimination” problem so that the resultant orbital renderings would look like solids. Lionel, and everyone to whom he showed the figures, including Roald Hoffmann, was excited to finally have 3-D views of molecular orbitals. I then spent much time in the summer of 1972 in the Aiken Lab making the orbital plots that were featured in the book with Lionel Salem, The Organic Chemist’s Book of Orbitals (Academic Press, 1973). When Roald received the Nobel Prize, I was asked to provide a plot of an MO of water to accompany the description of his work in the New York Times. Paul Schleyer and Ken Houk were also great fans of the book and plots, reflecting the strong visual sense of organic chemists. Bill Lipscomb liked the plots, too, and asked me to do the MOs of diborane for a review article that he wrote. R. B. Woodward was also always friendly to me. When the book was published, I brought him a copy in his wood-paneled office. As I was walking back to the basement of Converse Lab, Dodie Dyer came after me because “Professor Woodward would like you to autograph the book.” My thesis committee consisted of Corey, Lipscomb, and Woodward. Back then, one did not meet with the committee until the very end; I did give a demonstration of my LHASA work to Lipscomb and Woodward together in the Aiken lab. There were many other memorable people and events. I interacted with the chemical physicists in Prince House including Klaus Schulten, Attila Szabo, Peter Rossky, Ron Levy, and Dave Case. Among events, Jerry Berson came from Yale to give a lecture series at MIT in 1974. This was like a descent from Olympus as his experimental work probing the Woodward−Hoffmann rules was at the zenith. He also had office hours, so I visited until he had had enough. I still have the notes from the lectures and interactions; on February 21, we discussed concerted decomposition of bridged azo compounds, which ended up as a topic in my first solo publication, a JACS paper in 1975.3 In my notes, I also see that Jean-Marie Lehn gave a lecture at Harvard on March 3, 1974 on structure and diffusion in liquids like pyridineno cryptates then.

■

PURDUE (1975−1990): CAMEO, CARBOCATIONS, AND MONTE CARLO The job market remained poor, so finding an academic job was difficult. Very fortunately, Purdue was interested in a physical organic chemist, which resulted in my only formal academic interview. I hit it off with people there including Dick Sneen (one of Corey’s first graduate students at Illinois), Harry 625




with many visitors. It became clear to me that the solvation issues were not well addressed with QM since there quickly became too many structures to explore and there was no thermal averaging. Simultaneously, publications by Enrico Clementi and coworkers on liquid water and hydrated ions caught my eye. They used ab initio derived potential functions in Metropolis Monte Carlo (MC) simulations to obtain fascinating structural results and details on the intermolecular and ion−molecule energetics. So, I read up on statistical mechanics and MC methods including the recent books by McQuarrie and Watts and McGee. Thus, I decided to embark on fluid simulations with dreams of modeling a wide range of chemistry and biochemistry including reactions in solution. My first NSF grant came in 1978 to help support this work. The arena was wide open since before the mid-1970s atomic-level computer simulations of fluids were largely restricted to atomic and diatomic systems. The first simulation of liquid water was not reported until 1969 and was a Monte Carlo study by Barker and Watts,8 which was followed by the MD simulations of Rahman and Stillinger in the early 1970s.9 It is notable that the state-of-the-art simulations of water in 1974 were performed for 216 molecules in a periodic cube for under 10 ps.9 In view of the above MC studies and those for methane in water by Dave Beveridge and coworkers10 and the ease of use of the NVT and NPT ensembles with MC, I initially pursued MC simulations rather than molecular dynamics (MD), which is most straightforward in the NVE ensemble. The work would be systematic starting from relatively simple systems and moving toward more complex ones. So, I sat down on a Saturday and wrote the initial MC code for pure liquids. A few detailed questions arose, and I remember making a phone call (no e-mail then) probably on Monday to John Valleau for clarification; I only met John a few years later in Toronto, but from the literature it was clear that he was an MC expert. The initial program, MCLiquid, over the years evolved into the general modeling programs BOSS (Biomolecular and Organic Simulation System) and MCPRO (MC for Proteins).11 The initial potential functions were developed a la Clementi from ab initio calculations on dimers, and results were reported for liquid hydrogen fluoride, water, ammonia, and methanol during 1978−1980.12 These were the first simulations for all of these liquids other than water, highly computer-intensive for their time, and yielded much novel detail on the structures and energetics of the liquids. In a 1979 JACS paper, I noted, “...a Monte Carlo run for 125 water molecules and 500 000 configurations requires over 50 h of central processor time on a CDC/6500”.13 An interesting footnote on Purdue’s CDC/6500, which was turned off in 1989, is that it is being restored in Paul Allen’s Living Computer Museum in Seattle. The control panel from the last computer that I used at Princeton, the massive IBM 360 Model 91, is also there.

Morrison, John Grutzner, and Phil Fuchs (a former Corey postdoc). Corey let me stay on as a postdoc until I left for Purdue in August 1975. I started my Assistant Professorship at age 25 with a start-up package of $15,000. An initial project was the development of the CAMEO program for predicting products of reactions given the starting materials and conditions, which had connections to LHASA, but the analyses were more mechanistic (Computer-Aided Mechanistic Evaluation of Organic Reactions). I managed to purchase a Texas Instruments computer and a Tektronix display with the start-up funds and a Dreyfus Teacher-Scholar Award. My first graduate student was Tim Salatin, who did a superb job with the initial program developments and graphics.4 (Since I have had about 150 coworkers, I will only be able to name a few; a full list is appended.) The CAMEO project was provocative as it made one think in depth about why organic reactions work and the competitions from side reactions. It provided valuable cheminformatics training, often leading to employment in the pharmaceutical industry, e.g., for Cathy Peishoff, Mark Bures, Ellen Laird, and Gigi Paderes. The last of 26 publications on CAMEO appeared in 1995.5 The organic synthesis section of NSF had supported the project from 1980; the program officer, John Showell, was a strong backer in view of the novelty. A difficult decision is always when to stop a successful activity in the face of managing a reasonable group size and the desire to pursue new interests. Simultaneously, in the early days at Purdue, I executed QM projects mostly on my own. Likely owing to the presence of H. C. Brown, I developed interests in homoaromaticity and unusual carbocations such as homocubyl. Herb and I got along well, though the discussions had to be about carbocations, especially related to 2-norbornyl. I gave him a framed rendering of the classical form’s LUMO, though he was not one to embrace MO concepts. Herb was classical in all ways. He also had many words of wisdom for his young colleague, things like “one idea, one paperyou don’t want to confuse your audience”, and he taught all squeakers how to hold a piece of chalk so that it would not. An unimaginable tradition today, Purdue until the mid-1980s had their organic seminars on Saturday mornings. Afterward the faculty and visitor would go to Sorrento’s restaurant for lunch. Since Sarah was absent, Herb and emeritus professor Bryant Bachman would always consume a large “deluxe” pizza. I am pretty sure that this is why at least Bryant, a really sweet man, came to the seminars. I also served as intermediary between Herb and Paul Schleyer, who was on the nonclassical side of 2-norbornyl and visited Purdue several times. There was associated massive written correspondence from Herb, the “Norbornyl Letters”, and his last book, The Nonclassical Ion Problem (Plenum, 1977). I was in California in October 1979 when Herb received the news of the Nobel Prize, so I went to a Western Union and sent him a congratulatory telegram. When I returned to Purdue, always practical Herb asked me, “Why did you do that?” That was my last telegram. The QM studies led to my wondering if addition of solvent molecules and counterions could influence the energy differences between open (classical) and bridged (nonclassical) carbocations.6 So, I performed QM calculations on clusters of carbocations with increasing numbers of solvent molecules such as HCl.7 The answer was yes for sufficiently nucleophilic solvents, which provoked debates with Paul Schleyer and Martin Saunders. I met Martin for the first time when I spent a summer month during 1978 visiting Paul, who had moved to Erlangen. Paul and Inge generously shared their “Wagner Villa”

■

FORCE FIELDS There was general awareness of the need for better, general force fields for use in the growing application of MC and MD simulations. In our case, the ab initio potential functions were sensitive to the computational level, time-consuming to generate, and did not adequately incorporate dispersion effects. The nonbonded terms, which largely determine important properties such as densities and heats of vaporization of liquids, were the key problem. I thought that for improved agreement with experimental properties of liquids it would be necessary to 626




derive potential functions by directly fitting to liquid-state data. With the computer resources in the early 1980s, the computational problem of performing iterative fluid simulations for the parameter optimizations was daunting. Running one MC or MD simulation could be sufficient for a publication at that time. We managed to purchase and implement our codes on some of the earliest minicomputers, a Harris 80 and Gould 32/8750 (I could not afford a DEC VAX-11/780), and we also had access to the CDC/6500 computer and eventually a Cyber 205. This enabled many computationally intensive undertakings beginning with the report in 1983 of the TIP3P and TIP4P models for water,14 which included comparisons with results for four other water models. I did the coding and iterative parametrization running many MC simulations on the minicomputers, one at a time, i.e., make a change, submit a job, come back the next day, look at the radial distribution function, density, and ΔHvap results, decide what to adjust next, and repeat. J. Chandrasekhar and Jeff Madura used the MC results to compute partial structure functions for comparison with neutron scattering data. Roger Impey and Mike Klein performed MD simulations for the TIPS2 and Bernal−Fowler water models so some results on diffusion constants could be added to the paper. The paper has been cited 15,000 times. The continuing stream of minor modifications to these models is interesting. It reminds me of a framed New Yorker cartoon that was in my parents’ home in Connecticut; it showed a couple gardening surrounded with rocks. The caption was, “I think Connecticut has probably been moved around more without getting anywhere than any other state in the Union.” The subsequent work on more than 100 organic liquids provided the basis for the OPLS (optimized potentials for liquid simulations) model for organic systems, proteins, and nucleic acids.15−17 Remarkably, this included the first simulations for liquid amides in 1985,18 even though MD simulations of proteins had been ongoing since 1977. Alternative potential functions well into the 1990s struggled with liquid densities since this property is very sensitive to the nonbonded parameters.19 With gratitude, I note that the NIH GM Institute has supported our work on force field development and biomolecular modeling since 1980. Julian Tirado-Rives joined the group as a postdoc in 1985 and led the developments for peptides and proteins; he has remained my closest associate ever since and is a Senior Research Scientist at Yale. He was much involved in the reports of the OPLS united atom and all-atom force fields in 1988 and 1996.15,16 His efforts at training new group members, answering daily questions, and managing our software and computers have been appreciated by all, and they have allowed me the freedom to remain engaged in programming and execution of projects.

also known as free-energy perturbation (FEP) theory (Zwanzig, 1954). Long-term goals for me were (a) computation of free energies of binding for host−guest systems and (b) modeling organic reactions in solution and eventually enzymatic reactions. In the latter case, a free-energy surface for the reaction and characterization of any intermediates and transition states was desired. Our earliest free-energy results came from direct sampling in pure liquid simulations; e.g., computing the population distribution s(φ) for the CCCC dihedral angle in butane gives the free-energy profile, ΔG(φ) = −kbT ln s(φ). Then, in 1981 with postdoc Bernard Bigot, who has recently been the high-commissioner of the French atomic energy commission (CEA), we developed umbrella sampling techniques to accelerate the convergence of such s(φ) for dilute solutions.22 An application in 1982 was for the anti/gauche equilibrium for butane, which showed increased gauche population in water vs the gas phase or neat liquid reflecting the hydrophobic effect.23 In 1984, my group then performed the first simulations for a bond making/breaking organic reaction in which changes in free energy of solvation were computed along the entire reaction path, specifically, the SN2 reaction of Cl− + CH3Cl, again with umbrella sampling.24 Jayaraman Chandrasekhar, whom I had met in 1978 in Erlangen, was an important contributor to this work; Chandru had two very productive stays in my group totaling about 6 years. The multiple MC simulations were made possible by Purdue’s acquisition of a Cyber 205 “supercomputer”. We modified BOSS to use the “vector processing” abilities of the Cyber 205 and got access to it in the break-in period. The SN2 work stimulated many related studies.25 Jiali Gao (now U. Minnesota), in the first wave of students from the PRC, was also a graduate student at the time and engaged in multiple projects including ion hydration; we had done what was likely the first simulation of a micelle in explicit water, but we did not publish it as I was concerned about stability/convergence. Flags should not be planted when they are wobbly, though there are many examples where this seems to pay off. Jeff Madura (Duquesne) and Jim Briggs (U. Houston) were at Purdue, too, and were involved in numerous publications on force-field development, solvent effects on reactions, and novel free-energy calculations like for the pKa of ethane and chloroform/water partition coefficients, and there were excellent Purdue undergraduates including David Spellmeyer and Jeff Evanseck, who went on for Ph.D.s with Ken Houk, and Scott Smith, who became a computer science professor at Johns Hopkins. In 1985, a profound event was the first FEP calculation for a molecular system in solution.26 I had decided to give this a try after reading a paper from the Berendsen group on noble gases in water and a conversation with Andy McCammon in Houston. Alternatives to umbrella sampling were certainly desirable since its need for biasing potentials required case-bycase treatment. It was unclear what pitfalls might arise or what the precision would be with FEP, but an exploration was warranted. The mutation of ethane and methanol in water was performed, allowing computation of their difference in free energies of hydration. I chose this pair owing to the significant changes in hydrogen bonding and ΔΔGhyd. New methodology was invented including what are now known as single-topology FEP calculations and double-wide sampling. The mutation was done in a series of steps or “windows” to enable proper convergence. A very exciting result was that the precision was excellent (±0.2 kcal/mol), which opened the possibility for

■

EARLY FREE-ENERGY STUDIES From the standpoint of applications, computation of freeenergy changes has central importance. Free energy determines equilibria and activation barriers for reactions. Thus, in the realm of liquid-state theory and biomolecular simulations, the development of methodologies for free-energy calculations and their applications have been key activities. Review articles are available for the early days; I wrote one in 1989, and Peter Kollman’s 1993 article in Chemical Reviews was comprehensive.20,21 The major methodologies that had emerged were umbrella sampling (Valleau, 1975) and the closely related importance sampling (Berne, 1979), thermodynamic integration (TI) (Kirkwood, 1935), and statistical perturbation theory 627




wide-ranging applications. As usual, I did the coding in BOSS, the lesson being that by having total familiarity with one’s own code one can readily implement and test new ideas. Subsequent early efforts by others did not include the on-the-fly averaging and windowing, just after-the-fact processing of saved MD configurations. Nevertheless, because the FEP calculations required about 6 weeks on our Harris 80 computer, the work was met with significant skepticism on practicality. A striking exception was Peter Kollman, who immediately grasped the significance of the preprint that I had sent him and embraced the methodology. He wrote a letter to me on June 27, 1985: “I also appreciated your nice preprint on CH3OH “mutation” to ethane in water. The results were most impressive and we have almost finished incorporating this λ perturbation method into the molecular dynamics module of AMBER, with the goal of studying site specific mutagenesis in trypsin.” Free-energy calculations were then widely pursued by us and others for proteins and organic host−guest systems.20,21 One enduring outcome of our MC/FEP investigations of nucleotide base pairs and related systems was the recognition of the importance of “secondary electrostatic interactions” for complexes with multiple hydrogen bonds including G−C and A−T pairs; it was possible to clearly rationalize previously confusing results on the strengths of alternative base pairs featuring two or three hydrogen bonds.27 My first public presentation on this occurred at a magical French−American Conference on Molecular Recognition at Château de Mavaleix organized by Jean-Marie Lehn (August 18−22, 1989). I was the first speaker and caused good buzz; simple models that work are always received well. Other host−guest luminaries in attendance included, in order of speaking, Peggy Etter, Julius Rebek (who brought Cuban cigars), Andy Hamilton, Francois Diederich, Ron Breslow, Peter Schultz, Jackie Barton, Peter Dervan, and Claude Helene.

water hydrogen bonding, and we noted good accord between computed sites for localized water molecules in comparison with those in the X-ray structure.28,29 Peter Kollman was also there. He had strong interests during the 1980s in developing the AMBER force field, free-energy calculations, and modeling DNA. In 1985, his group reported a 114 ps MD simulation of the Dickerson dodecamer in a cluster of 830 TIP3P water molecules.31 This was the first simulation of a DNA duplex in water using a reasonable model and simulation protocols.

■

YALE (1990−PRESENT)

■

PROTEIN UNFOLDING AND PCs

I will always be extremely grateful to the faculty and staff at Purdue for their unwavering support. My personal assistants there, Brenda Zika and Marilyn Barefoot, were also wonderful. The opportunity to move to Yale arose during 1989 and involved a visit with the organic and biophysical faculty including Marty Saunders, Sam Danishefsky, Jerry Berson, Ken Wiberg, Harry Wasserman, Alanna Schepartz, Mike McBride, Fred Ziegler, Don Crothers, and Jim Prestegard. Peter Moore was the Chairman, but Sam, of course, was also on the phone. They were simultaneously trying to hire K. C. Nicolaou, who instead chose fledgling Scripps. In view of the strong physical organic tradition and my New England roots, a group of 14 moved from Purdue in July 1990. Paty Morales became my assistant at this time and has been essential to the group and me ever since. The transition was quick, though our new, raised-floor computer lab in the Sterling building would not be completed for a couple of years. The principal activities were continuation of the CAMEO project, force field development, and simulation work on host−guest systems, organic reactions in solution, and proteins in water. My first new Yale graduate student was Erin Duffy in 1990, and Heather Carlson arrived in 1991. They were both very productive and versatile. Erin worked on multiple projects including solvent effects on amide isomerization, OPLS-AA for hydrocarbons, interactions with urea, and multiple host−guest systems; subsequently, we collaborated on predictions of pharmacological properties including solubility that were important in the development of the QikProp program. Heather worked on charge models, linear response calculations, solvent effects on the chorismate rearrangement, and cyclophane−steroid complexes. I was also delighted by the good news from Stockholm for E. J. Corey in October 1990. Again, I was on a trip, but this time just sent a letter.

■

MOLECULAR DYNAMICS FOR BIOMOLECULES IN WATER The value of performing MD simulations for a biomolecule without explicit treatment of the surrounding water is open to question. Water is needed for proteins to fold, it has profound effects on electrostatic interactions (screening) and dynamics (damping), and it is well-documented in crystal structures that specific water−protein interactions are apparent through hydrogen bonding and hydrophobic clustering. Efforts to include explicitly hundreds or thousands of water molecules in MD simulations began slowly in view of the computational demands. Initial reports came from Julian and me, Levitt, Berendsen, and coworkers, and the Lund group (Ahlström, Teleman, Jö nsson). This is nicely documented in the Proceedings of the Nobel Symposium No. 71 on “Structure and Dynamics in Biological Systems”.28−30 The meeting took place at Snogeholm Slott on December 6−9, 1989. It was a stimulating meeting in a beautiful setting with most of the leading research groups represented. We reported results of a 100 ps MD simulation of the 56residue silver pheasant ovomucoid with 1721 water molecules using periodic boundary conditions and our TIP3P and OPLSUA force fields,28 while Michael Levitt reported results of 210 ps MD simulations of BPTI in vacuum and with 2607 water molecules using Lifson’s protein force field.29 My across-thehall colleague at Purdue, Michael Laskowski, spent his career studying ovomucoids, thus, the choice. Both studies focused on convergence of the calculations and intraprotein and protein−

The possibility of protein structure prediction or protein folding by MD was obvious. The ca. 1 ms or greater time scale remains a serious practical problem. It occurred to me that simulation of the opposite process, protein unfolding, could be tractable at elevated temperatures and could provide insights into the mechanism of protein folding by time reversal. I had mentioned this to several people including Martin Karplus when I was a visiting professor at Harvard in 1989. To begin, Julian and I published MD results in April 1991 for the thermal denaturation of a 15-residue analogue of the S-peptide of ribonuclease A including 892 TIP3P water molecules.32 There was much interest in peptides that contained stable elements of secondary structure at that time; key experimental work came from the groups of Baldwin, Wright, and Kallenbach. The peptide was known by CD to be ca. 45% helical at 276 K and unstructured above 333 K. With OPLS-UA, we obtained good 628




Alder reactions and Claisen rearrangements was elucidated and helped set a foundation for the current activity in developing chiral hydrogen-bond donors as asymmetric catalysts. Bruce Ganem’s compliments on our Claisen work40 were gratifying: “With remarkable prescience, Severance and Jorgensen forecast that their results would ‘promote catalyst designs that incorporate two or more hydrogen-bond-donating groups positioned to interact with the oxygen in the transition state.’ This prediction was to be borne out with startling correctness in the detailed structure investigations of the active site of natural E. coli and B. subtilis chorismate mutase that were reported shortly thereafter.”41 In the studies through 1997 our quantum and statistical mechanics were decoupled; we determined a minimum-energy reaction path in the gas phase and then computed the relative free energy of solvation at each point. A goal was to perform the QM and MM simultaneously in on-the-fly “QM/MM simulations”. Different people have different definitions of QM/MM simulations. To me it means that when running an MD or MC simulation, every time the QM part of the system is altered, a new evaluation of the QM component of the energy is required. If an MC or MD simulation is not involved, e.g., it is just an energy minimization, then it is not a QM/MM simulation. I object to the increasingly common use of “simulation” as synonymous with “calculation”; a simulation requires configurational (MC) or time (MD) averaging. Our first QM/MM simulations were achieved in 1998 when George Kaminski helped implement semiempirical MO calculations in BOSS,42 and early applications were for Diels−Alder reactions and the chorismate rearrangement. Cognizant of the sampling demands and need for enhanced accuracy, our group, especially Matt Repasky and return visitor J. Chandrasekhar, pursued improved semiempirical QM methods resulting in PDDG/ PM3.43 There was much trial and failure along the way. The PDDG/PM3/MM approach has yielded accurate results for free energies of activation of numerous organic reactions in many solvents including SN2, SNAr, and Diels−Alder reactions, Kemp and other decarboxylations, Cope eliminations, and deaminations.38 These studies provided a wealth of details on the reaction mechanisms, solvent effects on the structures of transition states, and differential solvation of reactants and transition structures. Our first study of an enzymatic reaction, the isomerization of a tetrapeptide catalyzed by FKBP, was performed by Julian and Modesto Orozco in 1993.44 Subsequent QM/MM efforts then addressed the mechanisms for chorismate mutase, macrophomate synthase, and fatty acid amide hydrolase (FAAH).45−47 Graduate student Ivan Tubert-Brohman and postdoc Cris Guimaraes were much involved in these studies and the associated development of PDDG/PM3. Notably, the results found that macrophomate synthase is a tandem Michael−aldolase rather than a putative Diels−Alderase.46a This prediction received subsequent experimental confirmation from Hilvert’s group.46c For FAAH, an unusual Ser-Ser-Lys proteinase, the order of proton transfers was clarified as well as the origin of amide/ester selectivity.47 In more recent work, we have interfaced BOSS with the Gaussian and GAMESS programs to allow use of ab initio and DFT calculations for the QM part of our QM/MM studies. Throughout the work on reactions in solution, I have enjoyed illuminating interactions with Ken Houk and Don Truhlar. Ken and I have shared interests in many areas and several publications on pericyclic reactions. Don and Chris

accord in a 300 ps run at 278 K and in a 500 ps run at 358 K. An interesting observation was that the formation and disappearance of main-chain helical hydrogen bonds occur through an α-helix ⇆ 310-helix ⇆ no hydrogen bond sequence. Related reports for other peptides followed, especially from the groups of Charles Brooks, David Case, Peter Kollman, and Michael Levitt. Case modeled an 18-residue peptide from myoglobin with 1049 TIP3P water molecules.33 Levitt’s initial publication in the area was for Ala13 in water at six temperatures for 200 ps.34 The peptide studies quickly led to work on protein denaturation in water. There were papers in 1992−1994 that used high temperatures (ca. 200−300 °C) to try to reach a molten globule state. Aside from the boiling issue, at such temperatures, helices rapidly decay, which can lead to a misleading view of late secondary-structure formation on folding. The first below-boiling effort to characterize a protein unfolding/folding pathway was the paper in 1993 by Julian and me on unfolding apomyoglobin in the presence of 5332 TIP3P water molecules.35 A 350 ps MD run was executed at 25 °C and two 500 ps runs were performed at 85 °C, yielding good agreement with experiment on the temperature dependence of the helix content. Then, in 1997, Julian, Modesto Orozco, who had been a visiting professor, and I published the first MD results for unfolding a protein, barnase, in aqueous solution containing the well-known denaturant urea.36 It was found that the first solvation shell of the protein is enriched in urea relative to the bulk solvent, and images of an unfolding transition state and intermediate agreed with experimental analyses by Fersht. At this point we turned to other interests; running long MD simulations with imperfect force fields was not an optimal activity. The protein folding problem was being flirted with but not solved. Meanwhile, Julian was also instrumental in our discovery of the utility of personal computers for molecular modeling, as reported in 1996.37 Previously, PCs were thought to be good for little more than word processing. However, we were curious, and Julian implemented BOSS on newly acquired Dell computers running the just-released Windows 95 with Intel Pentium processors. The speed of the PCs was remarkable in comparison to much more expensive workstations from DEC, SGI, Sun, and HP, which were widely used for computational chemistry at that time. The paper concluded: “The 200 MHz PentiumPro is faster for BOSS calculations than the R8000 Power Indigo2. Considering the relatively low cost of the Pentium systems, they are an alternative worth further exploration.” I remember discussions with my good friend Rich Friesner on the results that evolved from disbelief to purchase of a large PC cluster at Columbia. Other people at the Gordon Conference on Computational Chemistry in 1996 were quite outspoken in their disbelief of my claims about PCs.

■

REACTIONS IN SOLUTION: QM/MM The simulation work on reactions in solution also advanced rapidly. Peter Kollman’s review can again be consulted,21 and Orlando Acevedo and I have written a recent one.38 Other active researchers in the field have published recent reviews as well.39 As noted above, our publications began in 1984 with report of free-energy profiles for the SN2 reaction of Cl− + CH3Cl.24 This was followed by numerous studies of other reactions in which we characterized the solvation of the reactants and transition states. The importance of hydrogen bonding for catalysis of pericyclic reactions including Diels− 629




promise of being the first new antibacterial class to treat modern superbugs since 1962. The Jorgensen synthesis group has grown to occupy three laboratories with 12 hoods and many expensive instruments that reinforce the appeal of computational chemistry. The greatest effort has been directed to discovery of improved NNRTIs. Karen Anderson, my stalwart colleague in the Yale School of Medicine, and her coworkers have performed biological assays on over 600 compounds that we have designed and synthesized in multiple chemical series. The challenges are great because the compounds need to be potent toward wild-type HIV-1 as well as multiple clinically important variant strains containing mutations to the reverse transcriptase (RT) enzyme. Good pharmacological properties are also required; poor solubility has been a recurrent problem with NNRTIs. A particularly notable achievement was our FEP-guided optimization of a 5 μM docking hit in an infected T-cell assay to yield a 55 picomolar inhibitor, the most potent known NNRTI.50 In collaboration with the Anderson group, we also reported the crystal structure for its complex with RT in JACS in 2012,51 which agreed closely with the model published in 2011. The design was exhaustive including FEP refinement of substituents and recognition of the benefits of changing the diphenylmethane core to a diphenylether. Analogues also show low-nM activity against clinically important variant strains of HIV-1 and solubilities in the normal range for drugs. The group’s efforts have become even more comprehensive in our work on discovery of inhibitors of human MIF, where the group has done protein expression, computer-aided design, synthesis, enzyme assaying, and protein crystallography. MIF is associated with numerous inflammatory diseases. Our principal activities have now turned to discovery of anti-cancer agents.

Cramer have helped us with atomic charge models, essential to describe electrostatics in our general OPLS/CMx force fields. Over the years, John Tully and Peter Rossky have also provided valuable interactions on statistical mechanics issues. Dale Boger, my Purdue colleague who moved to Scripps, has been an important collaborator on the studies of FAAH and also on investigations of vancomycin analogues.48 Very sadly, my regular interactions with Peter Kollman ended on May 25, 2001. My last e-mail from Peter was on May 11; it begins, “Thanks for your kind words, Bill...as one of your earliest mentors, it has always been a source of pride to me what you have accomplished...I plan to fight this thing the best I can.” There is a photo of Peter and me from the 1996 Gordon Conference on Computational Chemistry in New Hampton, NH that I am very fond of and that can be seen on my group’s website. Peter spoke in the section on “Critical Analysis of Methodology for Free-Energy Calculations”. We also both spoke at the first GCCC in August 1986 at Colby-Sawyer College. Peter was always a wonderfully engaging, dynamic presence.

■

COMPUTER-AIDED DRUG DISCOVERY Though expectations arose in the 1980s for the utility of FEP calculations in the design of enzyme inhibitors, little progress was made for 20 years. The FEP approach was too computationally intensive for routine use given the computer resources available before ca. 2000. However, starting in the mid-90s our group has actively pursued MC/FEP calculations for numerous protein−ligand systems. With optimized protocols, improved force fields, and greater automation, confidence arose to undertake inhibitor design. It was important to determine if FEP calculations actually had prospective value. I recognized that the group would have to be responsible for both the computations and synthesis for reasonable progress to be made. My background with Corey and constant involvement with organic reactions made me confident that I could manage both activities. The first synthetic postdoc, Juliana Ruiz-Caro, was hired in 2004. The initial project was the design and synthesis of nonnucleoside inhibitors of HIV reverse transcriptase (NNRTIs). Andy Hamilton, who moved to Yale in 1997 before sojourning to Oxford in 2009, kindly agreed to provide her with lab space. By this time, I had written the BOMB and QikProp programs, which were used for de novo design and prediction of pharmacological properties. (The original version of QikProp was written in all-night sessions on a visit to Hong Kong, where I was experiencing time-inversion.) The de novo design was then augmented by FEP calculations to refine the choices for heterocycles, linkers, and ring substituents, that is, to guide lead optimization. The complete suite of drug-design software (BOSS, MCPRO, BOMB, QikProp) was also important in providing the computational platform to complement the ribosome crystallography in the founding of Rib-X Pharmaceuticals by Peter Moore, Tom Steitz, Susan Froshauer, and me in 2001. As documented now in numerous publications,49 our computer-guided approach has been highly successful for multiple targets including HIV-RT, human and Plasmodium macrophage migration inhibitory factor (MIF), FGFR1 kinase, and p53/hDM2. Our software has also been successfully used at Rib-X (now Melinta Therapeutics) for many projects including the design of the antibacterial agent radezolid, which has been in phase-II clinical trials and for what has the

■

CONCLUDING REMARKS Our investigations of intermolecular interactions have evolved from QM studies of solvated carbocations in the 1970s to FEPguided design and synthesis of enzyme inhibitors. Much had to be invented along the way. Such evolution is necessary for thriving in the scientific world. I always view successful careers like marathonsone has to keep at it mile after mile with the big picture in mind. Fortunately, the evolution is great fun as one gets to learn new things, interact with many stimulating people, and make one’s own contributions to expanding the frontiers of knowledge. Of course, the advances from my laboratory would not have been possible without the great efforts of ca. 150 group members. In the end, my greatest success and joy have been in helping facilitate their professional lives. I am also very grateful to the funding agencies, especially the NSF, NIH-GM, and NIAID for steady support. The multifaceted contributions from Purdue and Yale have been essential, and the American Chemical Society is also thanked for their tireless efforts in promoting our field including via their journals, meetings, and awards program.

■

ADDENDUM: EARLY HISTORY I was born in New York City on October 5, 1949. My father, Axel V. Jorgensen (1912−1996), immigrated to the U.S. from Denmark in 1935; he worked his entire career for the Danish engineering firm, F. L. Smidth, mostly in midtown Manhattan. He spoke six languages and received a B.A. in economics from NYU at night. His father was a train conductor. My mother, Alice Lane Jorgensen (1911−1990), grew up in Spokane, WA 630




(17) For a review, see: Jorgensen, W. L.; Tirado-Rives, J. Potential energy functions for atomic-level simulations of water, and organic and biomolecular systems. Proc. Nat. Acad. Sci. U.S.A. 2005, 102, 6665− 6670. (18) Jorgensen, W. L.; Swenson, C. J. Optimized Intermolecular Potential Functions for Amides and Peptides. Structure and Properties of Liquid Amides. J. Am. Chem. Soc. 1985, 107, 569−578. (19) Kaminski, G.; Jorgensen, W. L. Performance of the AMBER94, MMFF94, and OPLS-AA Force Fields for Modeling Organic Liquids. J. Phys. Chem. 1996, 100, 18010−18013. (20) Jorgensen, W. L. Free Energy Calculations, A Breakthrough for Modeling Organic Chemistry in Solution. Acc. Chem. Res. 1989, 22, 184−189. (21) Kollman, P. A. Free Energy Calculations: Applications to Chemical and Biochemical Phenomena. Chem. Rev. 1993, 93, 2395− 2417. (22) Bigot, B.; Jorgeensen, W. L. Sampling Methods for Monte Carlo Simulations of Normal-Butane in Dilute Solution. J. Chem. Phys. 1981, 75, 1944−1952. (23) Jorgensen, W. L. Monte Carlo Simulation of n-Butane in Water. Conformational Evidence for the Hydrophobic Effect. J. Chem. Phys. 1982, 77, 5757−5765. (24) Chandraskhar, J.; Smith, S. F.; Jorgensen, W. L. SN2 Reaction Profiles in the Gas Phase and Aqueous Solution. J. Am. Chem. Soc. 1984, 106, 3049−3050. (25) For example: (a) Bergsma, J. P.; Gertner, B. J.; Wilson, K. R.; Hynes, J. T. Molecular dynamics of a model SN2 reaction in water. J. Chem. Phys. 1987, 86, 1356−1376. (b) Bash, P. A.; Field, M. J.; Karplus, M. Free Energy Perturbation Method for Chemical Reactions in the Condensed Phase. J. Am. Chem. Soc. 1987, 109, 8092−8094. (c) Hwang, J.-K.; King, G.; Creighton, S.; Warshel, A. Simulation of Free Energy Relationships and Dynamics of SN2 Reactions in Aqueous Solution. J. Am. Chem. Soc. 1988, 110, 5297−5311. (26) Jorgensen, W. L.; Ravimohan, C. Monte Carlo Simulation of Differences in Free Energies of Hydration. J. Chem. Phys. 1985, 83, 3050−3054. (27) Jorgensen, W. L.; Pranata, J. The Importance of Secondary Interactions in Triply Hydrogen-Bonded Complexes: GuanineCytosine vs. Uracil-Diaminopyridine. J. Am. Chem. Soc. 1990, 112, 2008−2010. (28) (a) Jorgensen, W. L.; Tirado-Rives, J. Molecular Dynamics Simulation of the Third Domain of Silver Pheasant Ovomucoid in Water. Chem. Scripta 1989, 29A, 191−196. (b) Tirado-Rives, J.; Jorgensen, W. L. Molecular Dynamics of Proteins with the OPLS Potential Functions. Simulation of the Third Domain of Silver Pheasant Ovomucoid in Water. J. Am. Chem. Soc. 1990, 112, 2773. (29) (a) Levitt, M. Molecular Dynamics of Macromolecules in Water. Chem. Scr. 1989, 29A, 197−203. (b) Levitt, M.; Sharon, R. Accurate simulation of protein dynamics in solution. Proc. Natl. Acad. Sci. U.S.A. 1988, 85, 7557−7561. (30) Ahlström, P.; Teleman, O.; Jönsson, B. Interfacial Water Studied by Molecular Dynamics Simulations. Chem. Scr. 1989, 29A, 97−101. (31) Seibel, G. L.; Singh, U. C.; Kollman, P. A. A molecular dynamics simulation of double-helical B-DNA including couterions and water. Proc. Natl. Acad. Sci. U.S.A. 1985, 82, 6537−6540. (32) Tirado-Rives, J.; Jorgensen, W. L. Molecular Dynamics Simulations of the Unfolding of an α-Helical Analogue of Ribonuclease A S-Peptide in Water. Biochemistry 1991, 30, 3864− 3871. (33) Soman, K. V.; Karimi, A.; Case, D. A. Unfolding of an α-Helix in Water. Biopolymers 1991, 31, 1351−1361. (34) Daggett, V.; Levitt, M. Molecular Dynamics Simulations of Helix Denaturation. J. Mol. Biol. 1992, 223, 1121−1138. (35) Tirado-Rives, J.; Jorgensen, W. L. Molecular Dynamics Simulations of the Unfolding of Apomyoglobin in Water. Biochemistry 1993, 32, 4175−4184. (36) Tirado-Rives, J.; Orozco, M.; Jorgensen, W. L. Molecular Dynamics Simulation of the Unfolding of Barnase in Water and 8 M Aqueous Urea. Biochemistry 1997, 36, 7313−7329.

and received B.A. and M.A. degrees from the University of Montana and Columbia Teachers College. Many of her relatives were homesteaders in Montana in the 1920s. My parents, brother, and I moved from Manhattan to Port Washington, L.I. in 1950, where I went through fifth grade in the St. Peter of Alcantara School. After my brother went to college in 1960, we moved to Sherman, CT. I went to the Sherman public school for sixth through eighth grade; there were 12 in my graduating class in 1963.

William L. Jorgensen

■

Department of Chemistry, Yale University

REFERENCES

(1) Davidson, R. B.; Jorgensen, W. L.; Allen, L. C. Structural and Energetic Predictions for Simple Hydrocarbons from the NDDO and CNDO Semiempirical Molecular Orbital Methods. J. Am. Chem. Soc. 1970, 92, 749−753. (2) Corey, E. J.; Wipke, W. T. Computer-Assisted Design of Complex Organic Syntheses. Science 1969, 166, 178−192. (3) Jorgensen, W. L. Chemical Consequences of Orbital Interactions. II. Ethylene and Butadiene Bridged Polycyclic Hydrocarbons Contain Three- and Four-Membered Rings. J. Am. Chem. Soc. 1975, 97, 3082− 3090. (4) Salatin, T. D.; Jorgensen, W. L. Computer Assisted Mechanistic Evaluation of Organic Reactions, l. Overview. J. Org. Chem. 1980, 45, 2043−2051. (5) Fleischer, J. M.; Gushurst, A. J.; Jorgensen, W. L. Computer Assisted Mechanistic Evaluation of Organic Reactions, 26. Diastereoselective Additions: Cram’s Rule. J. Org. Chem. 1995, 60, 490−498. (6) Jorgensen, W. L. The Similarity of Solvent Effects on Carbocations. J. Am. Chem. Soc. 1977, 99, 280−281. (7) Jorgensen, W. L.; Munroe, J. E. The Influence of Increasing Solvation on the Relative Energies of Bisected and Bridged Ethyl Cations. Tetrahedron Lett. 1977, 99, 581−584. (8) Barker, J. A.; Watts, R. O. Structure of Water; A Monte Carlo Calculation. Chem. Phys. Lett. 1969, 3, 144−145. (9) Stillinger, F. H.; Rahman, A. Improved simulation of liquid water by molecular dynamics. J. Chem. Phys. 1974, 60, 1545−1557. (10) Swaminathan, S.; Harrison, S. W.; Beveridge, D. L. Monte Carlo studies on the structure of a dilute aqueous solution of methane. J. Am. Chem. Soc. 1978, 100, 5705−5712. (11) Jorgensen, W. L.; Tirado-Rives, J. Molecular Modeling of Organic and Biomolecular Systems Using BOSS and MCPRO. J. Comput. Chem. 2005, 26, 1689−1700. (12) Some examples for HF, water, ammonia, and alcohols: (a) Jorgensen, W. L. Monte Carlo Simulations of Liquid Hydrogen Fluoride. J. Am. Chem. Soc. 1978, 100, 7824−7831. (b) Jorgensen, W. L. Minimal Basis Set Description of the Structure and Properties of Liquid Water. J. Am. Chem. Soc. 1979, 101, 2016−2021. (c) Jorgensen, W. L.; Ibrahim, M. The Structure and Properties of Liquid Ammonia. J. Am. Chem. Soc. 1980, 102, 3309−3315. (d) Jorgensen, W. L. Transferable Intermolecular Potential Functions. Application to Liquid Methanol Including Internal Rotation. J. Am. Chem. Soc. 1981, 103, 341−345. (13) Jorgensen, W. L. Quantum and Statistical Mechanical Studies of Liquids. 4. Minimal Basis Set Description of the Structure and Properties of Liquid Water. J. Am. Chem. Soc. 1979, 101, 2011−2016. (14) Jorgensen, W. L.; Chandrasekhar, J.; Madura, J. D.; Impey, R. W.; Klein, M. L. Comparison of Simple Potential Functions for Simulating Liquid Water. J. Chem. Phys. 1983, 79, 926−935. (15) Jorgensen, W. L.; Tirado-Rives, J. The OPLS Force Field for Proteins. Energy Minimizations for Crystals of Cyclic Peptides and Crambin. J. Am. Chem. Soc. 1988, 110, 1657−1666. (16) Jorgensen, W. L.; Maxwell, D. S.; Tirado-Rives, J. Development and Testing of the OPLS All-Atom Force Field on Conformational Energetics and Properties of Organic Liquids. J. Am. Chem. Soc. 1996, 118, 11225−11236. 631




(37) Tirado-Rives, J.; Jorgensen, W. L. Viability of Molecular Modeling with Pentium-Based PCs. J. Comput. Chem. 1996, 17, 1385− 1386. (38) Acevedo, O.; Jorgensen, W. L. Advances in QM/MM Simulations for Organic and Enzymatic Reactions. Acc. Chem. Res. 2010, 43, 142−151. (39) (a) Warshel, A. Molecular Dynamics Simulations of Biological Reactions. Acc. Chem. Res. 2002, 35, 385−395. (b) Gao, J.; Ma, S.; Major, D. T.; Nam, K.; Pu, J.; Truhlar, D. G. Mechanisms and Free Energies of Enzymatic Reactions. Chem. Rev. 2006, 106, 3188−3209. (c) Senn, H. M.; Thiel, W. QM/MM Methods for Biomolecular Systems. Angew. Chem., Int. Ed. 2009, 48, 1198−1229. (40) Severance, D. L.; Jorgensen, W. L. Effects of Hydration on the Claisen Rearrangement of Allyl Vinyl Ether from Computer Simulations. J. Am. Chem. Soc. 1992, 114, 10966−10967. (41) Ganem, B. The Mechanism of the Claisen Rearrangement: Déjà Vu All Over Again. Angew. Chem., Int. Ed. Engl. 1996, 35, 936−945. (42) Kaminski, G. A.; Jorgensen, W. L. A QM/MM Method Based on CM1A Charges: Applications to Solvent Effects on Organic Equilibria and Reactions. J. Phys. Chem. B 1998, 102, 1787−1796. (43) Repasky, M. P.; Chandrasekhar, J.; Jorgensen, W. L. PDDG/ PM3 and PDDG/MNDO: Improved Semiempirical Methods. J. Comput. Chem. 2002, 23, 1601−1622. (44) Orozco, M.; Tirado-Rives, J.; Jorgensen, W. L. Mechanism for the Rotamase Activity of FK506 Binding Protein from Molecular Dynamics Simulations. Biochemistry 1993, 32, 12864−12874. (45) Guimaraes, C. R. W.; Repasky, M. P.; Chandrasekhar, J.; TiradoRives, J.; Jorgensen, W. L. Contributions of Conformational Compression and Preferential Transition State Stabilization to the Rate Enhancement by Chorismate Mutase. J. Am. Chem. Soc. 2003, 125, 6892−6899. (46) (a) Guimarães, C. R. W.; Udier-Blagovic, M.; Jorgensen, W. L. Macrophomate Synthase: QM/MM Simulations Address the DielsAlder versus Michael-Aldol Reaction Mechanism. J. Am. Chem. Soc. 2005, 127, 3577−3588. (b) Wilson, E. Is the Case for a Diels-Alderase Dead? Chem. Eng. News 2005, May, 38. (c) Serafimov, J. M.; Gillingham, D.; Kuster, S.; Hilvert, D. The Putative Diels−Alderase Macrophomate Synthase is an Efficient Aldolase. J. Am. Chem. Soc. 2008, 130, 7798−7799. (47) Tubert-Brohman, I.; Acevedo, O.; Jorgensen, W. L. Elucidation of Hydrolysis Mechanisms for Fatty Acid Amide Hydrolase and Its Lys142Ala Variant via QM/MM Simulations. J. Am. Chem. Soc. 2006, 128, 16904−16913. (48) Leung, S. S. F.; Tirado-Rives, J.; Jorgensen, W. L. Vancomycin Resistance: Modeling Backbone Variants with D-Ala-D-Ala and D-AlaD-Lac Peptides. Bioorg. Med. Chem. Lett. 2009, 19, 1236−1239. (49) Jorgensen, W. L. Efficient Drug Lead Discovery and Optimization. Acc. Chem. Res. 2009, 42, 724−733. (50) Bollini, M.; Domaoal, R. A.; Thakur, V. V.; Gallardo-Macias, R.; Spasov, K. A.; Anderson, K. A.; Jorgensen, W. L. ComputationallyGuided Optimization of a Docking Hit to Yield Catechol Diethers as Potent Anti-HIV Agents. J. Med. Chem. 2011, 54, 8582−8591. (51) Frey, K. M.; Bollini, M.; Mislak, A. C.; Cisneros, J. A.; GallardoMacias, R.; Jorgensen, W. L.; Anderson, K. A. Crystal Structures of HIV-1 Reverse Transcriptase with Picomolar Inhibitors Reveal Key Interactions for Drug Design. J. Am. Chem. Soc. 2012, 134, 19501− 19503.

632


Autobiography of William L. Jorgensen: Scientific History and

Recommend Documents