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I T,.ch. >I J Head Gordon. M lhrlu. O W . Fwcman. J 5: Srhlcgel, H 8 : ~ n ~ h. h b~b M ~A B~N ~ W ~C Y J hs .(ionrn~ex.c ~ ~ .~ ~ k. r ~~ eJ rF. ~~ . D J .\Vh#tpadr. H A . % ? f i r . R . M c l ~ u s . C . F : S s k ~ r ..JM a n ! n . H I.. K.4hn.l.R . 31cworl J J I,:nplo~ S . P+.. .I A c ~ . ~ ~ ~ I . A Nand oI, scralon3 Gaussian:Pittsburgh, 19m. 2. Kmplus, M.;Pater, R. MAfom ond Mokulos;W . A Benjamin: NY, 1970. 3. McWeeny, R. Coulsonk Vale-; W o r d University, 1979. 4. A full bibliography of ealeulations on the hydmpn molecule to 1980 is given in: M c k a n , A. D.; Weisa, A,: Yoshimhe, M. hu.Mod. Phys. 1960,32,211. Reference to individualeahlations (by author and year)cited in t h e k t are homthir bibliograph~ 5. Sloeh, F 2.Physik 1928,52,555. 6. Mulliken, R. S.Phya. h v . 1928,32,186,388,761:1029,33,607,730. 7. LennardJones, J. E. Pam. Fomd. Sae 1029.25.668. 8. Kauzmann, W.Quonfum Chomistry;Academie: New York, 1957:Chapter 12. 9. Hehre. W J.; Radom, L.;Schleyer, P. v. R.; Pople, J. A.Ab inirio mokulorarbitd I h r y : John Wlley and Sans:New Yo* 1986.
Teaching Molecular Modeling An Introductory Course for Chemists, Implemented at the Universite de Montreal Hermann Dugas Un vers re de Montreal Monrrbal. Oueoec. Canada H3C 3J7
General Approach in Molecular Modeling With the outcome of more sophisticated theoretical methods of calculation and the accessibilitv of com~utational resources, computational chemistry has now been accepted as a useful and powerful tool in research for industry as well as for the academic wmmunity. Molecular modeline of a molecule bv com~utereenerallv implies a graphics'presentation of t6e geometry or the c&fi&ation of the atoms of the molecule followed, if no data from crystallography are available, by the application of a theoretical method, like ab initio quantum mechanics, semiempirical quant;m mechanics or molecular mechanics, to evaluate the physical properties of the molecule under study. Computational chemistry is thus a discipline that is based on concepts of theoretical chemistry and computer science and ax such became in recent years a usefulcomplement to classical experimentation. This approach does hot intend to replace experiments but is aimed a t analyzing results more critically, at proposing a n interpretation of physiwchemical phenomena, and a t suggesting new experiments. Any simulation of a process is called modeling and the manifestation of such simulation is called a model. As t simulate some such. molecular modeline is an a t t e m ~to molecular properties in order to nndektand them better. In other terms. it correswnds to the numerical determination of structural properties, energetics and/or dynamics of a molecular svstem through a model based on the ensemble of the geometric confi&ations ohtained from a digital calculation. One of the objectives of molecular modeling is to reproduce and predict &alitatively, and possibly q&ntitatively, the physicochemical behavior of molecules and macromolecules. Molecular simulation should, for example, allow the evaluation of the difference in energy between conformers, the effect of solvent on conformations or on a reaction, the difference in energy between molecular complexes, ete. Not o d y theoretical chemists but also crystallographers, spectroscopists, inorganic chemists, organic i s t ~ chemists, biochemists and b i ~ o r ~ a n i c ~ h e mpolymer and pharmacologists have reasons to be interested in molecular modeling. The following enumeration gives some of the objectives of molecular modeling in chemishy.
Some Objectives of Molecular Modeling in Chemistry Computer graphics viauslization and desi~mof rnulecules from structural data using rhe facility of n computer Use eumouterircd srruc~urnldata banks to rdentlh, molecular systems with common points. Use empirical force fields to determine molecular properties as well as atomic distances. Correlate molecular properties with a given electronic structure. .Gain information on dynamic molecular movements and their energies. Apply the design of molecules by computer to molecular recognition in organic, bioorganic, and medicinal chemistry as well as material sciences. For this, different techniques of visualization, manipulation. analysis and calculation of molecular structures are known. ~ i h e m a t i c a l lone ~ , distinguishes the techniques of molecular graphics allowing a representation on a screen of the 2D or 3D structure of a molecule, its manipulation (rotations, translations, superpositions, changes in conformation, etc.) in an interactive way and the possibility to analyze its molecular coordinates (evaluation of geometric such as distances, angles, accessible surfaces, etc.). These structures can be obtained by constmction from elements (atoms. emuns. nucleic acid or peptidie residues) taken frbm a ~r&r~m'library. In some cases, they are extracted from crvstalloera~hicdata banks: CamS D rookh ) haven Protein Data bridge Structural D ~ ~ ~ C & Bank (PDB). In other cases, they are constructed from experimental results, that is from X-rays or NMR data. To pass from an initial model to a fmal one, many steps of optimization must be overcome with the use of different techniques of calculation like molecular mechanics and/or molecuiar dynamics. These methods constitute a semnd aspect of molecular modeling. They are based on the use of different software to evaluate energies, to do simulations, and to simulate molecular motions Purpose and Goal of the Course I t is with these objectives, just outlined above, that a course in molecular modeline was develo~edrecentlv a t the Universitb de Montrbal. it is an introductory co&e where the ma1 is to allow our eraduate students in chemistry, biochimistry, and pharmacology to familiarize themselves with computational chemistry. The aim is to lay down in a simple way the concepts of ionic and molecular interactions through methods of molecular simulation applied to organic and bioorganic molecules. Particular attention is given to molecular mechanics calculations that provide useful information concerning variation in potential energy as a function of variation in molecular stmcture. The focus here is mainly with organic and bioorganic molecules. I t is hoped also that through such exercise, the students will benefit from a better understanding of stereochemistry and conformational analysis. Materials for the Course and Evaluation of Students' Performance This one-semester course is given for a period of three hours ner week where the students can mani~ulatedifferent sokware on the screen. They have access to either an Evans and Sntherland PS-390, wnnected to a micro-VAX 3500, (for MacroModel) or four Silicon Graphics Personal IRIS (for MacroModel and Chiron). Four IBM-PC (for PCModel and REACCS) and two Macintosh MAC11 (for REACCS and Chemprotekt) are also available. The wurse is given mainly to graduate students in chemistry but students from other departments also are welcome. In addition, it is offered as an optional course to fmal-year undergraduate students in chemistry with a particularly good background in organic chemistry. Relevant textbooks on Volume 69 Number 7 July 1992
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molecular m o d e l i n g a n d d m g design a r e recommended a n d ulaced o n reserve a t t h e c h e m i s t w l i b r a m (1-7). A complete set o f lecture notes (typed-polycopy, 494 pp, in F r e n c h only) i s available a t m i n i m a l cost t o t h e students attendine t h e course (8). . . Finallv. -,there i s a constant evalua t i o n o f t h e performance o f each student with a specific software (namely Chiron, PC-Model, o r MacroModel) in front of t h e computer a n d 50% o f t h e total m a r k i s allocated in t h e f i n a l evaluation for t h i s practical section of t h e course. Furthermore, as p a r t o f t h e final examination, students are asked to a w r i t t e n summary of a pertin e n t article chosen f r o m a substantial l i s t o f subiects dist r i b u t e d for t h a t purpose. F o r example, each student h a s to select a n artic1e;read it, construct t h e molecule o n screen, m i n i m i z e i t s structure a n d evaluate dihedral aneles a n d other values cited in t h e article. T h e actual articles are as diverse as c r o w n ether chemistry (9), cephalosporin derivthromboxane ), analogues atives (101, r e n i n inhibitor (ll (12) a n d p-turn m i m i c (131,t o cite a few. The students have over a m o n t h to prepare t h e i r projects a n d t h e i r w r i t t e n reports. T h e p r a d ~ c a l - t e s to r evalu&on o n t h e cornouter i s done i n d i v i d u a l l"v b "v t h e urofessor responsible during t h e l a s t week of t h e semester
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Supplement (I h, if time permits) Chapter 5 Conformational Analysis of Peptides and Molecular Modeling --design of peptidomimetic molecules Chapter 6 NMR and Molecular Modeling of Peptide Chains --algorithm of distance-geometry -NOE effect and the design of peptide mimics -the CAVEAT3 approach this program was developed in P. A. Bartlett's group (Berkeley) and allows a search through the CSD bank for molecules to match an enzyme active site's coordinates for the design of a specific inhibitor. It is referred to as the Computer-Assisted Vector Analysis of Taget. For more information,consult reference 5, pp 182-1 96.
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Course Outline T h e following outline h a s been followed i n presenting t h e course where t h e typed polycopy i s divided into 10 chapters Theoretical Section (15 h of lecture) Chapter 1 lntroduction to Molecular Modeling (2 h) -notions of molecular structures and analysis of molecular movements i n t e r n a l molecular energy and the importance of molecular simulation Chapter 2 Overview of Various Software for the Chemist (2 h) 4AS-ONLINE, SYNLIB, REACCS.' ORAC 4 a t a banks: PDB, CSD stereochemist and strategy in organic synthesis using CHIRON and CHEMPROTEKT.' These programs have been developed at the Universith de Montrbal in S. Hanessian's group and both will be used by the students. -examples of software for molecular modeling: MODEL, MACROMODEL, SYBYL, BIOGRAF, QUANTNCHARMM. Only the first two will be used in the practical session. Chapter 3 lntroduction to the Methods of Energy Minimization (8 h)
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- e m p r cal representation of molec~larenergy and the oillerent force f~elds -the methodologies of molecular mechanics steepest descent conjugate gradient Newton-Raphson simulated annealing --the principles of molecular dynamics basic principle possible applications -Monte Carlo simulations application to proteins conformational analysis and municonformer search Chapter4 Molecular Modeling in Medicinal Chemistry (2 h)
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-modeling of small molecules and macromolecules -drug-receptor interaction and rational drug design 4 S A R and molecular liwphilic potential
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Practical Section (24 h of computer time) Chapter 7
Strategy in Organic Synthesis and the use of CHlRON2 (6 h) Each student aets a chance to become familiar with verson 4 21-01 the sohware on a ?dl con Grapncs star on or w th tne Mac~nroshverslon Two recent an c es (14.15) on th~sprogram are ~ n c t ~ o eindtne lecture notes. Chapter 8 Utilization of PC-MODEL4 (6 h) The students construct histamine and cyclohexane derivatives, measure barriers of rotation, and are doing MM2 calculations. Other examples like the Curtin-Hammen orincioie are also used. Both IBMPC version 89 ( ~ e r e n aSoftware) and the latest VAX version 2.96 of MODEL are available. MODEL is continuously being developed by K. Steliou from our department. Chaoter 9 Utilization of MACRO MODEL^ (12 h) Versions 3.0 and 3. IX of the software are available on either Evans and Sutherland or Silicon Graphics workstations. Exercises similar to those on MODEL are carried out with MACROMODEL and examples of batch minimization are presented. More emphasis is given here to peptide and nucieic acid chemistry. The students are asked to read the Appendix D first. References Chapter 10 In this last chapter of the typed polycopy, a list of books, review articles and referencespertinent to each subiect of the orevious chaoters is aiven. Comolement Append~xA:VMS ana U h X env ronments. Tne oas c commanos for botn of these environments are given. Appendix B: The article by D. B. Boyd and K. B. Lipkiwitz, "Molecular Mechanics: The Method and its Underlying Philosophy"; J. Chem. Educ. 1982, 59,269-274. Appendix C: The article by M. Karplus and G.A. Petsko, "Molecular Dynamics simulation in Biology"; Nature 1990, 347, 631448. Appendix D: The article by W. C. Still eta!., "MacroModeCAn Integrated Software System for Modeling Organic and Bioorganic Molecules Using Molecular Mechanics"; J Comp. Chem. 1990, 11. 44G467. ' D m buted by Molec~ar Des gn L mtted. San Leandro. CA, USA. 2Dtstr buted by S. danessan, J n versitb de Montreal. Queoec, Canada. 3Distributed by the University of California. Berkeley, CA, USA. 4Distributedby SerenaSoftware, Box 3076. Bioomington, IN. USA. 'Distributed by Columbia Univemity, New York, NY, USA.
Organization of the Course
The first four chapters of the text cover the theoretical background necessary to do molecular modeling. At the end of this section a series of tables summarizing the advantages and disadvantages of each algorithm are available as well as a list of criteria where molecular modeling is appropriate or not. Chapters five and six are regarded as more specific subjects and are treated only if time permits. These subjects are referred to as supplements to the first four chapters. The focus is more on conformational analysis of peptide bonds. Extra material for reading is also available in the Appendices and comes from review articles taken from the recent literature. Actually, the course is divided in two parts. Atheoretical section (15 h) and a practical section (24 h) where the students have a chance to spend some time in front of the graphics stations. For this, the class is divided into four small groups of three students and in order to give access to all the groups to the graphics stations, a sufficient number of three one-hour periods (one afternoon)is allocated to each group. There are also three teaching assistants available to help any one in difficulty; one for PC-Model, one for Chiron, one for Chemprotekt and REACCS, plus myself for MacroModel. Hanessian and Steliou also are invited to participate in the course and to present, respectively, their programs. Using a grid of four p u p s , each with three students, the 13 weeks of the semester are divided in the following way: during the first week, only theory (3 h) is given. For the next four weeks, two hours of theory and one hour of practice on the computer is given to each group, in rotation. That is while one group gets instructions on MacroModel, the second one is on PCModel, the third one on Chiron, and the last one on Chemprotekt. ARer four weeks, each group had one hour tutorial on each of the four software. In the following four weeks, there is only one hour of lecture and two hours of practice where the accent is given again on MacroModel, PC-Model and Chiron plus, this time, the data bank REACCS. Again, there is a rotation of each group. Finally, for the last four weeks of the semester, the three one-hour periods are devoted entirely to practice on the computers where they complete their individual pmject . All the computers are on the same floor (in two different rooms) except for the PS-390 and two IBM that are in another mom, one floor up. The students are even encouraged to come to the computer rooms at hours outside the
normal schedule time to complete their personal work if necessary. Conclusion
In summary, this course serves as an initiation to the utilization of soRware to solve problems of svnthesis and structure in organic and bioorg&ic chemist6 We present promams designed to use data from the literature and others to evaluateaspects of stereochemistry for the planning of organic synthesis (CHIRON) as well as for choosing the best protecting groups (CHEMPROTEKT).A large part of the course is devoted to software that uses molecular mechanics andlor molecular dynamics to analyze the energetics and the dynamics of molecules (MODEL, MACROMODEL). A particular accent is put on medicinal applications and the concept of structure-activity relationship. If a student has an interest in a specific class of molecules, drugs or hormones, he or she has the possibility (if time permits) to develop a small project or assignment around these compounds by constructing molecular models, performing energy minimization calculations and reviewing the literature concerning the molecular basis for biological activity, if applicable. Such experience or exercice can even be carried on to their own research. The increasing demand on trained chemists with a good knowledge ofmolecular modeling in many fields of chemistry and biochemistry served as an incentive to develop such a course. Literature Cited 1. WiLson, S Chemishy & Computer:An Ouemiew ofthe Applieollona ofcomputere in Chamist?y: Plenum:New York, 1986. 2. P e m , T J. ; Ropst, C. L., Eds. Computer-AidedD~ugDe~~is, DeLLer: New York,
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8. Vsnhtaradaran. B.:Feldmann.R. , J.. Eds. MocmmoleularStrutruL~m~dSsiff. ily:Compuler.Assis~MdeliqandAppl'cofions.Ann.N.YAead. Sd.439.1985. I. Beveridge, D. I . ; Jolgenaen,W. L., Eds. Computer Simulation of Chemical ond Blamolpeular Syafem, AM. N.Y.Aead. Sei. 482,1988. 8. Dugas, H. M d l i s o l i a n Moldculoim, SWdoehimb a Anolyse C o n f o m l i o n m l b , tibrawe de I'UniversiM de Montr6al. 1991. 9. EEhogoyen,L.;Pama,D.;Bertalotti,L.J.; Ha*, C.;Gokel, G. W J. Coard. Cham. ~~~
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15. Haneaman, S.;Franco, J.:Gagna, 6:Laramee.D.: Iamuehe, B.J. ~ k & . In,! Comput. Sei. 1990.30.413-425.
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