Section 20.2.1. Introduction

Molecular dynamics (MD) is the simulation of motion for a system of particles. Advances in the theory of atomic interactions and the increasing availability of high-power computers have led to rapid development of this field and greater understanding of macromolecular motions. In the earliest molecular-dynamics simulations of protein molecules (McCammon et al., 1977; McCammon & Harvey, 1987), the systems were greatly simplified in order to fit within the computing capabilities of that time. Simplifications included the exclusion of water molecules and even of explicit hydrogen atoms; the effect of hydrogen atoms was built into the heavy-atom properties using so-called extended-atom parameters. Simulation time periods were limited to tens of picoseconds for systems of less than 10³ atoms. Modern simulations, by contrast, are based on improved force fields (MacKerell et al., 1998) and benefit from considerable development in algorithms. In addition, the possible size and time period of simulations have increased by orders of magnitude; large systems of the order of 10⁴ atoms (including explicit solvent molecules) and nanosecond time periods are accessible. With dedicated computer time, the microsecond regime is possible (Duan & Kollman, 1998). Interestingly, the first 100 ps simulation of an enzyme complex was of hen egg-white lysozyme (Post et al., 1986), the first enzyme whose structure was solved by X-ray crystallography. Then the simulation required several months of dedicated time on a Cray supercomputer, but now it can be accomplished in less than a week on a common workstation.

A consequence of this enormous growth in computing power has been the particularly successful application of molecular dynamics of biological molecules to three-dimensional structure determination and refinement. It is now practical to use molecular dynamics, in combination with crystallographic and NMR data, to search the large conformational space of proteins and nucleic acids to find structures consistent with the data and to improve the agreement with the data. The advantages of molecular dynamics over manual rebuilding and least-squares refinement are the abilities to overcome the local minimum problem in an automated fashion and to search the complex conformational space of a macromolecule more extensively (Brünger et al., 1987).