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All-Atom Empirical Potential for Molecular Modeling and Dynamics Studies of Proteins

Why this mattered

This paper mattered because it helped turn atomistic protein simulation from a specialized, often system-specific craft into a more general empirical modeling platform. The CHARMM22 all-atom protein parameters were not just a parameter list; they embodied a disciplined strategy for balancing bonded terms, electrostatics, van der Waals interactions, solvation behavior, small-molecule thermodynamics, peptide conformational energetics, crystals, and full protein simulations in one self-consistent force field. That balance was the paradigm shift: the paper made clear that fitting isolated quantum-mechanical data alone was insufficient for biological molecular dynamics, because a useful protein force field had to reproduce condensed-phase behavior and experimentally observed protein structure and dynamics.

After this work, it became much more plausible to simulate proteins as physical molecular systems rather than as coarse structural cartoons or ad hoc energy-minimization targets. The parameters supported all-atom molecular dynamics of folded proteins, peptide crystals, backbone and side-chain conformations, and protein environments in a way that could be compared systematically with experiment. In combination with CHARMM parameters for nucleic acids and lipids, the paper also helped enable broader biomolecular simulations in which proteins could be studied alongside membranes, ligands, solvent, and other biological components under a unified empirical potential.

Its influence is visible in the later expansion of molecular dynamics into protein folding studies, conformational ensemble modeling, membrane-protein simulation, ligand-binding thermodynamics, and mechanistic interpretation of structural biology data. The later breakthroughs depended not only on faster computers and better sampling algorithms, but on force fields trusted enough to make long simulations scientifically interpretable. With more than fourteen thousand citations, MacKerell and colleagues’ 1998 paper became one of the central foundations for that trust: it defined a practical standard for how biomolecular force fields should be parameterized, validated, and used as instruments for molecular explanation.

Abstract

New protein parameters are reported for the all-atom empirical energy function in the CHARMM program. The parameter evaluation was based on a self-consistent approach designed to achieve a balance between the internal (bonding) and interaction (nonbonding) terms of the force field and among the solvent-solvent, solvent-solute, and solute-solute interactions. Optimization of the internal parameters used experimental gas-phase geometries, vibrational spectra, and torsional energy surfaces supplemented with ab initio results. The peptide backbone bonding parameters were optimized with respect to data for N-methylacetamide and the alanine dipeptide. The interaction parameters, particularly the atomic charges, were determined by fitting ab initio interaction energies and geometries of complexes between water and model compounds that represented the backbone and the various side chains. In addition, dipole moments, experimental heats and free energies of vaporization, solvation and sublimation, molecular volumes, and crystal pressures and structures were used in the optimization. The resulting protein parameters were tested by applying them to noncyclic tripeptide crystals, cyclic peptide crystals, and the proteins crambin, bovine pancreatic trypsin inhibitor, and carbonmonoxy myoglobin in vacuo and in crystals. A detailed analysis of the relationship between the alanine dipeptide potential energy surface and calculated protein φ, χ angles was made and used in optimizing the peptide group torsional parameters. The results demonstrate that use of ab initio structural and energetic data by themselves are not sufficient to obtain an adequate backbone representation for peptides and proteins in solution and in crystals. Extensive comparisons between molecular dynamics simulations and experimental data for polypeptides and proteins were performed for both structural and dynamic properties. Energy minimization and dynamics simulations for crystals demonstrate that the latter are needed to obtain meaningful comparisons with experimental crystal structures. The presented parameters, in combination with the previously published CHARMM all-atom parameters for nucleic acids and lipids, provide a consistent set for condensed-phase simulations of a wide variety of molecules of biological interest.

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