A giant's shoulders: a Perspective from Professor Norman L. Allinger

If we can see further into the details of molecular structure, it is because we are standing on several strong sets of shoulders, of which Norman ‘‘Lou’’ Allinger’s are one. Many of us remember the days when small molecule modeling was done almost solely with his ‘‘MM’’ series of programs, MM1, MM2, MM3, MM4 which Lou painstakingly parameterized for the particular chemical functionality of his research efforts. Far from the high dollar efforts and software industry we see today, Lou’s software and molecular mechanics efforts never received funding; they were a labor of love piggy-backed on larger research efforts. He made source code available to anyone who wanted it and charged only a few thousand dollars to industrial users. Anyone interested in computational chemistry had—any many still have—a copy of ‘‘Burkert and Allinger’’ on their shelves. Now we are lucky that decades later Lou has sacrificed his retirement from The University of Georgia to provide us with a new edition. It is fair to say that without Lou’s contributions the field of computational chemistry would be years behind where it is now. In this issue Lou continues to teach and is good enough to provide his Perspective on today’s role of molecular mechanics in this era where we almost blindly press a button to generate thousands of conformations of hundreds of thousands of molecules and simulate systems comprised of tens-to-hundreds of thousands of atoms. He reminds us of the hard work and detailed study that goes into getting the structure of just one bond or functional group correct and he allows us to infer the heartaches that can arise in this pursuit. He cautions us that quantum mechanics not only still does not fulfill our structural (not to mention temporal) needs, but also does not provide the chemical, structural, and physical insight that teaches us chemistry. We are implicitly reminded that as we push that button we should pay attention to the hard truth that there is still work to be done and there may lay inaccuracies underneath that button. In particular, Lou notes that the force fields so carefully crafted for the modeling of proteins are not crafted to meet the challenge of the greater chemical diversity of drugs or other molecules. Lou takes us through the history and philosophy of the field and gives us specific examples of how molecular mechanics can help us understand structural chemistry. He refreshes us on the underpinnings of the science and mathematics of molecular mechanics. He illustrates the physical chemistry of molecular structure and provides examples of how physical phenomena affect 3D atomic structure. There is no one better than Lou to guide us in this study. With their permission we provide part of an exchange between a knowledgeable reviewer and Professor Allinger which highlights some of the gems to be found in his Perspective: