Molecular dynamics simulations and drug discovery

Richard Feynman, recipient of the 1965 Nobel Prize in Physics, once famously stated: 'If we were to name the most powerful assumption of all, which leads one on and on in an attempt to understand life, it is that all things are made of atoms, and that everything that living things do can be understood in terms of the jigglings and wigglings of atoms.' Much of the biophysics of the last 50 years has been dedicated to better understanding the nature of this atomic jiggling and wiggling. The quantum-mechanical laws governing motions in the microscopic world are surprisingly foreign to those familiar with macroscopic dynamics. Motions are governed not by deterministic laws, but by probability functions; chemical bonds are formed not mechanically, but by shifting clouds of electrons that are simultaneously waves and particles. As Feynman eloquently put it, this is 'nature as she is - absurd' [1].Understanding these absurd molecular motions is undoubtedly germane to drug discovery. The initial 'lock-and-key' theory of ligand binding [2], in which a frozen, motionless receptor was thought to accommodate a small molecule without undergoing any conformational rearrangements, has been largely abandoned in favor of binding models that account not only for conformational changes, but also for the random jiggling of receptors and ligands [3-7].The mollusk acetylcholine binding protein (AChBP), a structural and functional surrogate of the human nicotinic acetylcholine receptor (AChR) ligand-binding domain [8-11], is one of countless examples that illustrate the importance of accounting for these atomistic motions (Figure 1). In crystallographic structures of small-molecule AChR agonists bound to AChBP, a key loop (loop C) partially closes around the ligand (Figure 1a,c). In contrast, crystal structures of large AChR antagonists like snake α-neurotoxins bound to AChBP reveal that this same loop is displaced by as much as 10 ？, producing an active site that is far more open (Figure