Prospects for Exploiting 4D Ultrafast Electron Microscopy in Solid

Prospects for Exploiting 4D Ultrafast Electron Microscopy in Solid-State Organic and Biological Chemistry† Kenneth D. M. Harris*,‡ and John Meurig Thomas*,‡,§,|

CRYSTAL GROWTH & DESIGN 2005 VOL. 5, NO. 6 2124-2130

School of Chemistry, Cardiff University, Park Place, Cardiff CF10 3AT, Wales, Department of Materials Science and Metallurgy, University of Cambridge, Cambridge CB2 3QZ, England, and Davy Faraday Research Laboratory, The Royal Institution, 21 Albemarle Street, London W1S 4BS, England Received July 27, 2005;

Revised Manuscript Received August 25, 2005

ABSTRACT: One of the most exciting recent experimental breakthroughs has been the development, by Zewail et al., of four-dimensional ultrafast electron microscopy (4D-UEM), which has the capability to combine direct spatial imaging of materials at angstrom resolution together with time resolution down to femtoseconds. We identify and discuss some of the wide-ranging future prospects for applying the 4D-UEM technique in organic solid-state chemistry, with reference to a variety of organic solids, including urea inclusion compounds, and in the study of biological materials such as ribosomes, proteins, and enzymes. 1. Introduction With the arrival of the recently described1 technique of four-dimensional ultrafast electron microscopy (4DUEM), in which the time domain is combined with the spatial one in such a manner as to achieve unprecedented real-time and real-space capabilities, it is appropriate that a number of investigations, not hitherto feasible, be now considered in regard to crystals both of relatively small organic molecules and of biologically significant macromolecular entities. First, however, it is appropriate to summarize the nature of 4DUEM and the kind of experiment that may be conducted through its agency. (A brief general outline of its potential has recently been given by one of us.2) We then consider a range of problems relating to organic solidstate chemistry, some of which were aired initially in the early work of J. M. McBride3,4 and, to some extent, by experiments carried out intermittently by us5-10 over the past 20 years. These problems relate to long-chain diacyl peroxides held as guest molecules in onedimensional tunnels in their inclusion compounds with urea. Finally, we adumbrate some investigations that, should they succeed, will be of particular relevance to some pressing current debates in macromolecular biochemistry. The key point to note with respect to both these areas of chemistry is that 4D-UEM would reveal both detailed structural and temporal analysis of the changes that the materials of interest undergo under a set of appropriate stimuli. 2. The Essence of 4D-UEM The fourth dimension (time) that Zewail et al.1 have added to the three spatial ones retrievable by high* To whom correspondence should be addressed. E-mail: [email protected] (K.D.M.H.); [email protected] (J.M.T.). † Dedicated to Professor Michael McBride on the occasion of his 65th birthday. ‡ Cardiff University. § University of Cambridge. | The Royal Institution.

Figure 1. Schematic diagram showing the design of the UEM instrument (OPO ) optical parametric oscillator).1 The inset shows the UEM image of a cell of rat intestine. The picture was kindly provided by V. A. Lobastov.

resolution electron microscopy was achieved via the use of coherent packets of electrons liberated from a photocathode with femtosecond laser pulses (Figure 1). In other words, theirs is a photoelectron microscope. A special feature of their design, which enables the photoelectrons to be accelerated to 120 keV, is that each packet may contain as little as one electron per pulse, a feature that ensures that no space-charge broadening

10.1021/cg050367l CCC: $30.25 © 2005 American Chemical Society Published on Web 10/12/2005

4D Ultrafast Electron Microscopy

of the electron beam occurs. The UEM of Zewail et al. provides, in principle, the ability to benefit from multiple pulsing with single-shot time resolution. Moreover, any reversible damage inflicted by an electron pulse on the irradiated sample may, by lengthening the interval between pulses, be allowed to self-heal in readiness for further repeated investigations. Further experimental details are given in the original paper,1 and a critique analyzing the potential of 4DUEM has also been given by one of us.2 Suffice it to say that the laser system used consists of a diode-pumped mode-locked Ti:sapphire laser oscillator which generates sub-100 fs pulses at 800 nm with a repetition rate of 80 MHz and an average power of 1 W. Part of the beam may be used to heat or excite the sample and to define the zero of time, while the remainder is frequencydoubled in a nonlinear crystal to yield 400 nm femtosecond pulses for generating the train of electron pulses. It should be feasible to follow directly the dynamic evolution of structure (of ribosomes, proteins, and a range of organic molecular crystals) and the concomitant charting of energy landscapes. If the suppression of electron-beam damage to be expected from the multiple and controlled pulsing (single-shot) approach described by Zewail et al.1 permits the collection of signals (diffraction patterns and images) at higher dose than has hitherto proved possible, then the sensitivity will be of huge consequence. We outline in the next two sections worthwhile and timely candidates for investigation. 3. Some Typical Issues in Organic Solid-State Chemistry Much of our present understanding of the nature of organic molecular solids has arisen from the application of X-ray diffraction techniques, on either single-crystal samples or powder samples (the capabilities of the latter having been subject to significant developments in recent years).11-14 However, while such techniques involving analysis of Bragg diffraction maxima provide valuable structural information, it is important to recall that this information is a space-averaged and timeaveraged representation of the actual material. Such descriptions of crystals as comprising an infinitely replicating array of identical unit cells containing motionless atoms and molecules may be adequate to answer some of the questions posed by solid-state chemists, but it is important to recall that such descriptions provide no information on the local spatial deviations that exist, beyond this averaged description, in the real material and no information on the time dependence of the structural properties (i.e. dynamics). Of course, progress beyond this approximation can be gained from studies of specific aspects of X-ray diffraction patterns, such as analysis of diffuse scattering to elucidate descriptions of disordered structures,15 careful analysis of temperature-dependent diffraction data to gain insights on dynamic trajectories,16-18 and studies that exploit the time structure of synchrotron radiation sources, allowing time-resolved X-ray diffraction studies (e.g. with picosecond time-resolution)19-22 or studies of species that have only transient existence (e.g. with nanosecond lifetimes).23 Electron diffraction techniques have also been exploited for time-resolved studies, on

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Figure 2. Illustration (from ref 28) of in situ time-resolved and spatially resolved monitoring of molecular transport in an organic solid using polarized Raman microspectrometry. The Raman micrographs shown were recorded during transport of pentadecane molecules through the channels of a porous crystal, displacing the molecules (1,10-dibromodecane) originally present within the channels. The probed region shown represents only part of the crystal, and the transport occurs from left to right (the pores run horizontally in the micrographs shown). Regions colored blue are rich in pentadecane; regions colored green are rich in 1,10-dibromodecane. The time taken to record each micrograph was ca. 28 min; the three micrographs shown were recorded (a) 18 h, (b) 29 h, and (c) 40 h after commencement of the transport process. Quantitative details of the spatial distribution of the pentadecane and 1,10-dibromodecane molecules, and its time dependence, are discussed in ref 28.

time scales ranging from milliseconds24 down to the much shorter time scales that can be reached using femtosecond pulses.25-27 To establish information on dynamic properties of organic molecular solids, a variety of spectroscopic techniques may be used, allowing the study of different types of dynamic processes occurring on different characteristic time scalessfor example, reorientational motions (e.g. using dielectric loss spectroscopy, solid-state NMR, quasielastic neutron scattering, etc.) and vibrational properties (e.g. using Raman and IR spectroscopy, Brillouin scattering, inelastic neutron scattering, etc.). However, these techniques inevitably involve spatial averaging, the extent of which depends on the particular technique; in some cases the spatial averaging occurs over the whole sample (single crystal or polycrystalline powder), whereas in other cases the spatial averaging occurs over a selected area of the sample probed by the incident radiation. In appropriate cases, such techniques may be used successfully to carry out spatially resolved and time-resolved studies of processes in organic solids (a recent example concerns the use of polarized Raman microspectrometry to study molecular transport in an organic material;28 Figure 2), but with spatial resolution and time resolution that are significantly different from those that are achievable by the 4D-UEM technique. In the example cited,28 the spatial resolution is of the order of tens of micrometers (both radially and axially, representing more than ca. 1012 unit cells in the sampled region) and the time resolution is of the order of several minutes. While appropriate combinations of the above diffraction-based and spectroscopic techniques have contributed significantly toward understanding structural and dynamic properties of organic solids, the new 4D-UEM technique has created unprecedented opportunities for probing the properties of materials with spatial resolution on the angstrom scale, coupled with time resolution in the femtosecond regime. We focus here on some of

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Figure 3. Photodecomposition of a diacyl peroxide molecule.

the many exciting prospects within organic solid-state chemistry that may now become feasible for study through the emergence of the 4D-UEM technique. 3.1. Photochemical Processes in Diacyl Peroxides and Other Materials. First, we return to the elegant contributions made by McBride and co-workers3,4 in the study of diacyl peroxide photodecomposition (Figure 3), which provided a number of insights of more general relevance to organic solid-state reactions. Among these, this work provided conclusive evidence that substantial local stress (of the order of tens of thousands of atmospheres) is generated at the site of photolysis (the fact that significant local pressures are generated in this case may be anticipated from the fact that four molecular fragments (two CO2 molecules and two alkyl radicals) are produced in the photodecomposition reaction and are constrained to occupy the region of space originally occupied by only a single molecule in the parent crystal). This system was studied by IR spectroscopy (the vibrational properties of the CO2 “dimer” provided a local probe of pressure at the reaction site) and EPR spectroscopy (which gave detailed geometric information on how the pair of alkyl radicals recoil from the reaction site in response to the stress generated). However, several key questions remain to be understood. For example, what happens to the surrounding regions of the crystal in the vicinity of the site of photolysisswhat structural deformations are introduced into these regions, and what is the spatial extent of these deformations? In particular, what are the time scale and mechanism for the propagation of these structural deformations? Also, how, in the femtosecond time domain, is the formation of these structural deformations correlated to the actual processes of breakage of the three individual bonds within the parent diacyl peroxide molecule? Furthermore, we may enquire whether the structural deformations are elastic in nature, such that the surrounding region of the crystal relaxes back to its original state once the stress is finally relieved. Instead, are defects such as dislocations introduced, which may have a further bearing on the properties of the photolyzed crystal? An equally important issue (see also refs 29 and 30) concerns the effect of long-range interactions between distant sites of photolysis and the percentage of reaction that the crystals can sustain before such interactions begin to play a role in influencing the reaction mechanism. All these questions could be answered directly by the application of the 4D-UEM technique, not only revealing structural details at atomic resolution but simultaneously establishing the time dependence of the structural changes. Chemical transformations in many other molecular crystals are similarly expected to be associ-

Figure 4. Structure of the hexadecane/urea inclusion compound at ambient temperature, showing nine complete tunnels (with van der Waals radii) viewed along the tunnel axis. The guest molecules have been inserted into the tunnels illustrating orientational disorder, in conformity with the observed X-ray diffraction data and results from spectroscopic investigations.

ated with the production of large stresses, such as the thermal decomposition of tert-butoxycarbonyl groups (as in the commercially important latent pigment material DPP-Boc),31,32 and would represent equally compelling examples for study. And, as identified elsewhere,2 the study of topochemical reactions in organic crystals (such as [2 + 2] photodimerization reactions in cinnamic acids and other materials)33 would represent an ideal opportunity to probe, on a spatially resolved and timeresolved basis, the local structural changes that arise in the crystal (both at the actual site of the dimerization reaction and in its close vicinity) in response to, and on the same time scale as, the reorganization of chemical bonds in the dimerization reaction. 3.2. Urea Inclusion Compounds: Chemical Reactions and Phase Transitions. Twenty years ago,5-10 we embarked on a wide-ranging set of studies of onedimensional tunnel inclusion compounds of urea (Figure 4), since these represent ideal single-crystal materials to explore the structure and dynamics of organic molecules incarcerated within a relatively rigid “porous” host, not unlike the situations that obtain in the chemistry of zeolitic materials (Figure 5 summarizes a range of guest species that are able to form urea inclusion compounds with the tunnel structure shown in Figure 4). We were prompted, in part, to undertake EPR spectroscopic measurements of various diacyl peroxides, which could be photolyzed to yield trapped alkyl radical pairs as in the studies of the pure crystalline diacyl peroxides carried out by McBride and coworkers discussed above. These diacyl peroxide/urea inclusion compounds were found to present a number of advantages over the pure crystalline diacyl peroxides,



Figure 5. Some typical examples of guest molecules that are able to form urea inclusion compounds with the “conventional” urea tunnel structure shown in Figure 4.

including the fact that the alkyl radical pairs produced in the urea tunnels were found to be stable to significantly higher temperatures (the alkyl radicals apparently do not react with the urea tunnels and are isolated from other diacyl peroxide molecules in adjacent tunnels) and the one-dimensional nature of the urea tunnel is such that the stress generated at the site of photolysis is relaxed predominantly in the direction of the tunnel, thus reducing the problem to one of one-dimensional character. A set of questions analogous to those posed above, particularly concerning the dynamics and mechanism of the production of local structural distortions in the vicinity of the site of photolysis, could again be addressed directly using 4D-UEM. However, an additional intriguing issue for diacyl peroxide/urea inclusion compounds concerns the fact that they have an incommensurate relationship6-9,34 between the periodicities of the host and guest substructures along the direction of the tunnel, such that different guest molecules along the tunnel experience a different local interaction with respect to the host structure; clearly this issue could have significant consequences concerning the structural deformations observed. It is now well recognized8,9,35,36 that urea inclusion compounds display a broad range of interesting physicochemical properties, several of which could benefit directly from the application of the 4D-UEM technique. These properties include the occurrence of orderdisorder phase transitions (studied extensively by X-ray diffraction and a wide range of spectroscopic techniques), which are associated with a structural distortion (symmetry reduction) of the host tunnel and orientational ordering of the guest molecules. More specifically, and taking the urea inclusion compound containing hexadecane guest molecules (see Figure 4) as a typical example, on passing below the phase transition temperature (at 150 K for this inclusion compound), the urea tunnel structure distorts from hexagonal to orthorhombic37 and there is an abrupt decrease in the motional freedom of the guest molecules38 (which, in the high-temperature phase, involves rapid rotation of the hexadecane molecule about its long axis on the picosecond time scale). However, details of the actual sequence of the atomic displacements that give rise to these structural transformations are not at all understood, including the important questions of how

Figure 6. Illustration of domain reorientation in a urea inclusion compound (containing 2,10-undecanedione guest molecules). (a) Optical micrograph of a single crystal of 2,10undecanedione/urea. (b) Schematic diagram showing the domain orientation (defined by the dipoles of the 2,10-undecanedione guest molecules) in the upper left portion of the crystal in (a). (c) Optical micrograph of the same single crystal during the application of fairly uniform stress along the (1 h ,1 h ,0) face (defined in (b)). (d) Schematic diagram showing the domain reorientation that has occurred within part of the crystal in (c). Data were taken from ref 41, courtesy of M. D. Hollingsworth.

“nucleation”39 of the phase transition occurs and the dynamic mechanism by which the structural changes then propagate throughout the crystal. The application of the 4D-UEM technique, with its unique capability to combine direct spatial imaging at atomic resolution together with sampling on a sufficiently rapid time scale, has the potential to enable mechanistic aspects of these phase transitions to be understood in unprecedented detail. Other more general aspects relating to nucleation of phase transitions in solids should also be directly amenable to answers provided by Zewail’s technique: for example, does nucleation decorate dislocation cores (as in some examples, notably acenaphthylene, of photodimerization reactions40), or does it lead to the multiplication of dislocations on well-defined slip planes? Equally interesting issues concern the atomic level detail and dynamics of domain-switching mechanisms in a family of ferroelastic urea inclusion compounds that Hollingsworth41,42 has studied in much depth in recent years (Figure 6). 3.3. Crystal Nucleation. Another area that we may highlight concerns the opportunity to apply 4D-UEM to establish dynamic and mechanistic details of crystallization processes. Although the goal of being able to exert control over crystallization processes is one of considerable current importance, from both fundamental43 and industrial44 perspectives, there remains (with some specific exceptions45) a significant lack of fundamental understanding of the critical nucleation stage of crystallization processes. The application of 4D-UEM

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to investigate molecular ordering processes in confined environments within porous materials,46 for example, would offer the prospect to gain novel insights into the early stages of crystal nucleation processes (such as the incipient formation of ice). The reverse process (melting in confined environments) has also gained much attention in recent years (reviewed elsewhere47) and would also be a fertile area for investigation using 4D-UEM. 4. Some Typical Issues in Solid-State Biological Chemistry It is prudent first to recall that 4D-UEM should have far-reaching value in the elucidation of at least three distinct areas that are of general biochemical interest: (i) macromolecular folding (in particular protein folding), (ii) enzymatic processes, and (iii) dynamical changes (and even mode of operation) of ribosome structures. After either a photostimulation (preferably) or a thermal pulse (via an absorbed photon flux) is delivered, there is every prospect that the mechanisms of action of such materials (especially the family of P450 cytochrome enzymes48,49) will be further elucidated. 4.1. Proteins. One of the major unsolved problems in biology at present is centered around the question of protein folding. No one knows, as yet, how to predict the 3D structure of a folded protein from its sequence of residues. In addition, given the amino acid residue sequence, how does the protein fold? This, too, is an unsolved problem. In the solid state, X-ray diffraction is the prime technique for determining the static structure of the protein. However, in solution, where the equilibrium between the unfolded and folded statess and even the partially folded intermediate statesmay be experimentally adjusted, the 3D structures of proteins in particular and biological macromolecules in general are retrieved largely from NMR measurements. Distance and torsion-angle constraints are extracted from NOE and J coupling data, respectively. Several methods of structure refinement for protein structure by NMR have been described.50-53 By careful choice of the protein to be investigated, new insights into conformation and dynamics during folding and unfolding by NMR have been gained by Gronenborn and co-workers.54 It is acknowledged55,27 that the current picture for protein folding and unfolding consists of the molecule undergoing dynamic motion on an energy landscape, which is assumed to resemble a funnel, with the bottom containing the folded protein in its native, stable conformation. In the course of unfolding, the molecule moves up the funnel and, in so doing, accesses more and more conformations until, at the top (in the unfolded state), a large number of conformations exist, with rapid exchange between them. Because of the dynamic nature of this situation, physical, chemical, and biological conditions (such as temperature, pH, amount of denaturant, and mutation) may be tuned so as to maximize the concentration of a particular state. Numerous such studies have been made, and NMR has been extensively deployed for such purposes. The fact remains, however, that the folding and unfolding mechanisms investigated this way are still a good way removed from the situation that exists inside the living cell. Almost nothing is known experimentally about how proteins fold within the cell.

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Of what value, therefore, will the 4D-UEM technique be in elucidating the fundamentals of folding and unfolding? We suggest that, initially, it might be profitable to undertake an experimental study of a chosen protein preserved by rapid freezing of crystals of it in aqueous films (or other, more appropriate solvents). The technique used by Milligan and Unwin,56 to identify the location of the exit channel in ribosomes, would be appropriate. However, since that time (1986), there have been many advances in cryoelectron microscopyssee, for example, the work of Wah Chiu et al.57 There could be several “starting points” for the original specimens the fully folded, partly folded, and completely unfolded protein could be held in a rigidified initial state, and then, by administrating a thermal pulse, the 4D-UEM could be used directly to image the ensuing sequence of dynamic changes. Another approach is to take a carefully chosen unfolded protein, in a kind of amorphous solid state, and then to observe the onset of folding stimulated by a thermal pulse or other excitation. (In general, application of heat denatures a protein; but some proteins can be induced to fold on application of heat.) 4.2. Enzymatic Processes. Only relatively rarely is it possible to deduce the mode of action of an enzyme from its static structure (derived from X-ray diffraction). While time-resolved Laue diffraction has proved very helpful, the prospect of being able to harness the full potential of 4D-UEM is especially promising. Ideally, one would be able to probe the reaction coordinate of an enzymatic reaction on the femtosecond time scale, so as to track the bond breakage and formation processes that are inextricably implicated in the catalytic action of the enzyme and to establish in detail the associated structural and conformational changes within the enzyme. Moreover, subtle changes in the atomic redistributions within the substrate bound to the catalytic site of the enzyme would also, under ideal circumstances, be accessible to the 4D-UEM method. 4.3. Ribosomes. Ribosomes are extremely important variants of ribozymes (catalytic RNA), being crucially involved in the translation of the genetic code so as to form an accurate sequence of peptide bond formations in the synthesis of proteins. A ribosome is, in effect, the protein-making machinery. The molecular mass of bacterial ribosomes is ca. 2.5 MDasin humans it is thought to be ca. 4.0 MDasand it is known that in a single bacterial cell there are some 50 000 ribosomes. With the comparatively recent availability of the (X-ray diffraction determined) structure of ribosomal particles,58-62 a good deal is now known about the process of rapid and highly regulated synthesis of proteins. These structural studies have also paved the way for the recent intense exploration of the docking and efficiency of various antibiotics at specific sites within the ribosome. Insofar as the molecular architecture of the ribosome is concerned, it is composed of two subunits, the socalled 50S (large RNA) subunit and the 30S (small RNA) subunit, and from top to bottom it measures some 250 Å. A solvent-accessible channel at the interface of the subunits is where molecules of aminoacylated t-RNA bind to the ribosomes. Three binding sites for t-RNA have been identified: the aminoacyl (A) site, the peptidyl (P) site, and the exit (E) site. These three sites


occur on both the large and small subunitssa helpful color picture of these sites within the ribosome is shown in Figure 1 of the paper by Puglisi, Chu, et al.63 The ribosome is a very flexible entity,64 and recent studies have focused upon the dynamics of the ribosome in the presence and absence of certain antibiotics. X-ray diffraction measurements reveal that there are several peripheral regions of the ribosome where considerable conformational flexibility occurs, the precise role of which is not yet known. As with other macromolecular systems of biochemical interest, notably intermembrane junctions, fluorescence microscopy has proved to be a useful technique. Two recent fluorescence imaging methods have proved particularly popular for real-time imaging of the dynamics of macromolecular entities. It is to be emphasized that these fluorescence imaging methods are tantamount to time-resolved, single-distance measurements, and they constitute only the initial steps in retrieving the whole picture of the dynamic processes occurring within the entire ribosome. Fluorescence resonance energy transfer (FRET) is especially sensitive to investigate spacings up to ca. 10 nm; reflection interference contrast microscopy (RICM) is another useful approach.65,66 Puglisi, Chu, et al.63,64 were able to monitor the realtime dynamic trajectories and to observe transient intermediates using single-molecule fluorescence resonance energy transfer (smFRET): they recorded by this means the time-dependent distances between donor and acceptor fluorophores attached to the so-called elbow region of the t-RNA molecules on the ribosome. To effect these studies, it was necessary to immobilize the ribosome, and this could be done by attaching it to a Langmuir-Blodgett layer, which is itself bound to a silica surface (such immobilization of the “translation machinery” does not perturb enzymatic t-RNA delivery to the A site, peptide bond formation, or translocation). These workers were able to compare earlier static pictures, derived from cryo-electron microscopy67 and X-ray diffraction,68 with their own dynamic (smFRET) studies of conformational fluctuations of t-RNA molecules, where continuous, dynamic exchange between discrete configurations in pre-translocation and posttranslocation states were observed.63 Static measurements using X-ray diffraction by Yonath and colleagues69,70 have shed much light both on the structural details of the ribosome itself and also on the docking of various antibiotics such as erythromycin, roxithromycin, clindomycin, and a new antibiotic, synercid, which has two components. Such studies have contributed greatly toward a deeper understanding of antibiotic action and resistance. Yonath’s X-ray diffraction studies have also uncovered the unexpected role of a particular nucleotide (adenine 2602), which seems to function as a kind of molecular propeller. Given that 4D-UEM is ideally suited to pursue direct measurements of the dynamics of the various components of the ribosome, it is highly desirable that such studies should be undertaken. Low-resolution microscopy played56 an important role early on in the identification of the protein exit tunnel, and higher resolution studies subsequently67,71 have added significantly to our appreciation of the statics of ribosome structure. It is clear, however, that a major field of modern structural


biology hinges on a deeper knowledge of dynamic changes in ribosome structures. 5. Concluding Remarks The examples highlighted in this article represent only some of the very wide range of problems that have the prospect of being elevated to a much higher level of understanding by the application of the 4D-UEM technique. We look forward, with much anticipation, to witnessing the advancement of several scientific frontiers through the application of this technique. 6. A Personal Tribute I (J.M.T.) wish to append a brief personal note to mark the occasion of J. M. McBride’s 65th birthday and to express my gratitude for the continuing friendship that Dr. McBride has extended toward me and my family. It was Mike McBride’s beautifully written paper72 that first made me aware of his elegance as an experimentalist. That paper on “Configuration, Conformation and Spin in Radical Pairs” had elicited the admiration of Schmidt and Cohen, and indeed it was they who drew it to my attention when I worked at the Weizmann Institute in 1969. Subsequently, Mike McBride and I met at an ACS meeting in New York City, and in due course, and to my great delight, he came as a Senior Visiting Research Fellow, sponsored by the U.K. Science Research Council, to my Department (of Physical Chemistry) at the University of Cambridge in 1980. Ever since, we have deepened our friendship and exchanged ideas; he looked after me graciously (and allowed me to sit for a while at J. Willard Gibbs’ desk) when I visited Yale as a Tetelman Fellow (at Jonathan Edwards College) in 1997. He also played a key part in directing Mark Hollingsworth as a postdoctoral fellow to Cambridge, and that gave rise to an extremely fruitful collaboration between Mark and the coauthor of this article, K.D.M.H. I have always admired the scholarly distinction, pedagogic skill, and exceptional historical awareness (of chemistry and numerous other cultural activities) that Mike McBride exhibits. Long may he continue to influence us alls young and old. Acknowledgment. We appreciate stimulating discussions with J. D. and E. V. Puglisi, A. H. Zewail, A. Yonath, A. M. Gronenborn, W. A. Eaton, and M. D. Hollingsworth. Professor Hollingsworth is also thanked for his involvement, as a colleague and collaborator, in our early research on diacyl peroxide/urea inclusion compounds. References (1) Lobastov, V. A.; Srinivasan, R.; Zewail, A. H. Proc. Natl. Acad. Sci. U.S.A. 2005, 102, 7069. (2) Thomas, J. M. Angew. Chem., Int. Ed. 2005, 44, 5563. (3) McBride, J. M.; Segmuller, B. E.; Hollingsworth, M. D.; Mills, D. E.; Weber, B. A. Science 1986, 234, 830. (4) McBride, J. M. Acc. Chem. Res. 1983, 16, 304. (5) Hollingsworth, M. D.; Harris, K. D. M.; Jones, W.; Thomas, J. M. J. Inclusion Phenom. 1987, 5, 273. (6) Harris, K. D. M.; Thomas, J. M. J. Chem. Soc., Faraday Trans. 1990, 86, 2985. (7) Harris, K. D. M.; Hollingsworth, M. D. Proc. R. Soc. A 1990, 431, 245.

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Prospects for Exploiting 4D Ultrafast Electron Microscopy in Solid

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