The first molecular dynamics simulation of a protein was reported in 1977. Martin Karplus published (Karplus, M. Biopolymers 2003, 68, 350) a brief history of molecular dynamics simulations of biological macromolecules, and of the period in his laboratory, during which time one of us (Levy) was a postdoctoral student in the group. It was difficult at the time to carry out molecular dynamics simulations of proteins using programs then available, and several members of the Karplus group at Harvard University discussed their ideas about how the situation might be improved.
The development of IMPACT began in the Levy group at Rutgers University, in 1985, starting with a core set of molecular mechanics energy subroutines used to carry out molecular dynamics simulations of proteins. Early research using IMPACT focused on the relation between simulations and NMR experimental studies of protein structure and dynamics, and on protein solvation. In 1992, the Center for Theoretical Simulation of Biological Systems was established by Richard Friesner at Columbia University and Friesner, Levy and Bruce Berne began to collaborate using IMPACT as a platform for methods development. In 1997, a strategic development partnership involving Columbia, Rutgers, Yale, and Schrödinger LLC was formed to provide a path for commercializing some of the new methods being developed for simulations of protein structural changes and interactions with ligands. Basic research projects have benefited from this partnership, particularly by the development of tools to automate the preparation of ligand–protein complexes, by the expanded coverage of the force field, and by the increased coordination between various modeling packages.
Molecular simulations of protein structural changes and ligand binding are built upon two foundations: (1) the design of effective potentials that are matched to the requirements of accuracy and speed appropriate to particular modeling problems; and (2) the design of algorithms to sample the effective potentials in highly efficient ways so as to facilitate the convergence of the simulations in a thermodynamic sense and/or the coverage over large databases containing structures for which effective potential energy calculations are required. Developing algorithms to satisfy the competing goals of accuracy and speed is at the heart of the problem when considering computational models for use in structural biology.
Since 2004 algorithm development within IMPACT has focused on the AGBNP series of implicit solvation models and a physics based model for estimating the free energy of binding of ligands to a protein receptor, the Binding Energy Distribution Analysis Method (BEDAM). The development of advanced sampling methods within IMPACT based on replica exchange has been central to this effort (see ASyncRE below). These projects have been carried out as a collboration between Levy, Emilio Gallicchio, with contributions from several of the students in the Levy lab during the period of 2004-2014.
For more information about the development of the molecular mechanics core technologies in Academic IMPACT, see: