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Special Issue Preface pubs.acs.org/JPCB
Tribute to William L. Jorgensen was visiting Harvard on sabbatical leave. The book contained a collection of three-dimensional drawings of molecular orbitals for simple organic compoundsimages that we now take for granted and are easily accessible on a device as simple as a mobile phone. At that time, however, there were no interactive graphics, and molecular orbitals were often plotted as abstract cross sections. These drawings provided a vivid illustration of a most important result from quantum chemical calculations, making such concepts as through-space and through-bond interactions and the Woodward−Hoffmann rules appear in front of our eyes. The impact of the graphics in this book on changing the then skeptical perception of computational chemistry is immeasurable, and it provided an early glimpse of the enormous influence of Bill’s research through its brilliant simplicity. Bill received his Ph.D. in 1975 under the tutelage of E. J. Corey, working on the LHASA project, an artificial intelligence program for retrosynthetic analysis based on the retrieval of information from a large database of known organic reactions. Corey was later awarded the 1990 Nobel Prize in Chemistry for the development of retrosynthetic strategy. Interestingly, the minded reader probably has noticed several big buzzwords above, far ahead of its time, which have become ubiquitous today. Bill was immediately recruited to Purdue University as an organic chemistry faculty in the Department, where he continued the AI project. Unlike LHASA, the strategy was taken in the forward direction following mechanistic rules and was called Computer-Assisted Mechanistic Evaluation of Organic reactions or CAMEO. Besides tinkering with organic chemistry on the computer, Bill did maintain an experimental laboratory for organic synthesis with hoods and many chemicals on the fifth floor of the H. C. Brown Building. One of the authors of this tribute (C.E.P.) initially split her time between the synthetic and computational sides of the research; however, the computational work began to far outpace the synthetic work, and Bill made the decision to close that side of the shop. Later, in 1982, another author of this tribute (J.G.) joined his group and wondered about the dark laboratory that he had to pass across every day before entering his office. With the help of a friend in the Ei-ichi Negishi group, a coupling reaction was carried out in the night, apparently successfully, using a solvent charged on an office supplies account. The latter, however, caught Bill’s attention, and the reaction was soon stopped and probably was the last synthetic chemistry experiment performed in his laboratory at Purdue. The importance of performing his own experiments to test and extend his computational predictions was clearly recognized, but the successful integration of experiment with computational predictions would only be fulfilled years later thanks to his efforts in the area of drug discovery. Bill’s early research at Purdue was concerned with homoaromaticity and carbocations by means of electronic
t is our great privilege to dedicate this special issue of The Journal of Physical Chemistry B to Professor William L. Jorgensen on the occasion of his 65th birthday. Bill’s work has broadly impacted both computational and experimental chemistry and biochemistry, often with piercing insights accompanied by characteristic simplicity. His scientific contributions range from quantum chemical and statistical mechanical simulations of condensed-phase systems to organic chemistry and pharmaceutical drug discovery. A central theme of Bill’s research is using computational techniques to bridge theoretical understanding and experimental observation. He pioneered free-energy simulations of chemical reactions in solution and, along the way, created some of the most widely used molecular mechanical force fields for liquids, solutions, and biopolymersthe paper on the TIP3P and TIP4P models for water has alone collected more than 15 000 citations. Bill is also a remarkable mentor. He has supervised more than 150 graduate students and postdoctoral associates, many of whom have gone on to influential positions in academia, industry, and government. In what follows, we highlight just a few of his many scientific contributions. In 1973, while he was a third-year graduate student, Bill coauthored the monograph The Organic Chemist’s Book of Orbitals with the French theoretical chemist Lionel Salem, who
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© 2015 American Chemical Society
Special Issue: William L. Jorgensen Festschrift Published: January 22, 2015 621
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every seminar speaker in the organic chemistry area who came to Purdue had something to say about the famous reaction profile, which has been reproduced on the front cover of this special issue. The picture that emerged from Bill’s simulation was clear: it is the stronger solvation effects on the chargelocalized nucleophile than that of the charge-delocalized transition state of the SN2 reaction that brings about an increase of ca. 20 kcal/mol in the free-energy barrier in water. This, in fact, was a long-held view from experiment and reaction field theory, but an explicit atomistic simulation using first-principles quantum mechanically derived intermolecular interaction potentials appeared to be truly convincing. It was said that a picture is worth a thousand words indeed. To this end, another example is illustrated by Bill’s concept of secondary electrostatic interactions to explain the strength of complexes that involve multiple hydrogen bonds, including C− T and G−A nucleotide bases. The development of a general and reliable method to compute free-energy changes is of central importance since they determine chemical equilibria and reaction rates. A number of techniques were already available, including umbrella sampling, which was used in the study of the SN2 reaction, and Widom particle insertion. The formula of statistical perturbation theory had long been established in the work of Zwanzig, and a couple of computer simulations on van der Waals spheres and halide ions had been carried out. It was Bill’s 1985 calculation of the difference in free energy of solvation between ethane and methanol in water that revolutionized condensed-phase simulations of chemical and biochemical transformations. The choice of the illustrative example in Bill’s study was critical. On one hand, it was simple enough to allow sufficient sampling to obtain converged results at that time, and, on the other hand, the compounds represented realistic molecules with both hydrophobic and hydrogen-bonding interactions. The key to success was that the relative free-energy change due to a small variation in the identity (i.e., force-field parameters) of two molecular species was determined in a common solvent configuration. Consequently, the large energy fluctuations from the bulk solvent cancel out, resulting in exceedingly more accurate results than were previously possible. The technique has become known as the free-energy perturbation (FEP) method. It has opened the possibility for a wide range of applications, including ligandprotein binding and inhibitor design, and it remains the central most important technique in computational chemistry and biochemistry, albeit with numerous enhancements. In 1990, Bill and his group moved to Yale University. It would have been a reasonably simple move for a theory/ computation group had he not been a meticulous organizer, insisting on keeping original records of computational results. The result was boxes of magnetic tapes, volumes of computer print-outs, and refrigerator-sized old computer cabinets. One collection deserving special mention included bags of computer punch cards that Bill had used when he first arrived at Purdue. It surely has become a profitable investment as computer punch cards have been a hot item on eBay. More seriously, the academic move transformed his focus toward developing methods and applications for biological systems, particularly in the area of drug design. He could certainly have used commercial software that were abundant by that time, but instead, Bill wrote by himself a series of computer programs to use in his studies, including BOSS, which has been developed at Purdue for FEP calculations, MCPRO (an unconventional
structure theory; however, the inadequacy of quantum chemical calculations on the latter system without including solvent effects motivated him to look beyond and has shifted his primary interest toward condensed-phase chemistry. By the end of the 1970s, Bill had already published a series of studies of organic and polar liquids through Metropolis Monte Carlo simulations employing the empirical potential energy functions that he had derived on the basis of quantum chemical calculations. At that time, computer simulation of chemical and biological systems was still in its infancy: Gelin, McCammon, and Karplus had just published the first molecular dynamics simulation of a protein without considering the solvent in 1979, and statistical mechanical simulations of condensed-phase systems were primarily limited to diatomic liquids and water. It was standard practice to use the results from quantum chemical calculations on configurations generated from Monte Carlo sampling to fit empirical potentials for these simulations. However, the quantum mechanical approaches were far from adequate to achieve the desired accuracy for modeling intermolecular interactions in the liquid. For example, a number of models for liquid water had been developed, but none of them could reproduce the experimental heat of vaporization and density. Consequently, these simulations were largely performed with fixed volumes. To improve the accuracy and transferability of the potential functions for intermolecular interactions, Bill decided that the force-field parameters should be fitted against key experimental observables directly using an ensemble that best mimicked the experimental conditions. Bill’s idea was simple; he made use of quantum chemical calculations to derive a set of parameters as the initial guess to perform liquid simulations using the isothermal−isobaric (NPT) ensemble and then iteratively optimized these parameters to reproduce the experimental structural and thermodynamic observables. The goal was to yield computational results within 3% of experimental data and within 1% for some key properties. This process, although timeconsuming, especially considering the computer speed of the 1970s and 1980s, produced highly accurate potential energy functions for a range of organic and inorganic liquids. So far, more than 100 liquids have been parametrized and are used to model solvent effects in these solutions. Assuming transferability, the functional groups of these liquids can be used to construct force fields for proteins, nucleic acids, lipids, and carbohydrates. The three-point charge (TIP3P) and four-point charge (TIP4P) modes for water published in 1984 have been widely used as the solvent model and as the anchor for developing force fields for biological systems. In fact, Bill’s optimization strategy has been adopted in the development of all modern force fields for biological systems. The availability of accurate force fields for liquids and solutions opened the possibility of quantitative investigations of intermolecular recognition, host−guest binding, and solvent effect on chemical reactions. Bill’s landmark study in 1984, with Jayaraman Chandrasekher and Scott Smith, on the exchange reaction between Cl− and CH3Cl on the SN2 mechanism in water, and later in dimethylformamide solution, not only generated a remarkable burst of novel methodology developments on the theoretical side, paving the way to studying a more complex and diverse range of chemical transformations, including enzymatic processes, but also truly convinced experimental organic chemists that computational chemistry can be useful and utilized for gaining a deeper understanding of reaction mechanisms. For the next several years, it seemed that 622
DOI: 10.1021/jp511519w J. Phys. Chem. B 2015, 119, 621−623
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Monte Carlo approach for simulation of proteins), BOMB (a novel molecular structure generator), and QikProp for property predictions to support drug development. These efforts were also helped by the tremendous increase in computer speed and availability of commodity hardware coupled to accurate force fields and reliable free-energy simulation techniques. Two early projects have already produced very promising results: the antibacterial agent radezolid has been in phase-II clinical trial through a joint venture of Rib-X pharmaceuticals cofounded by Bill and his Yale colleagues, and the design and optimization of HIV reverse-transcriptase inhibitors have yielded a 55picomolar compound thanks to his FEP calculations. The ability for theoreticians to perform accurate calculations and predict active compounds is often not sufficient to convince experimentalists to make the effort to synthesize and test the molecules. Bill returned to the vision he had since the beginning at Purdue (far before the community talked about “misty laboratories”) to set up an experimental laboratory to transform in silico models into real molecules. The remarkable results of ultrapotent inhibitors were predicted, synthesized, and optimized in his own lab supported by collaborations on biological activity testing. Bill has opened many frontiers in computational chemistry and has transformed the field to become an integral part of experimental organic and medicinal chemistry. He has moved the field one step forward in the direction of Lavoisier’s dream “to submit the bulk of chemical phenomena to calculation”. His past, present, and future accomplishments continue to have an impact on generations of chemists. We shall not conclude this brief tribute without expressing the deep appreciation for the impact that Bill has made in our careers and those of all of the members of BJ’s group. In many ways, Bill Jorgensen has been a model for us. Being in his laboratory has been a privilege and an outstanding opportunity to witness his scientific visions, his passion for chemistry, and his attention to the details. Thank you and happy birthday, Bill.
Jiali Gao University of Minnesota and Jilin University
Modesto Orozco University of Barcelona
Catherine E. Peishoff GlaxoSmithKline
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DOI: 10.1021/jp511519w J. Phys. Chem. B 2015, 119, 621−623