Empirical Force-Field Assessment: The Interplay Between Backbone Torsions and Noncovalent Term Scaling.

Eric J. Sorin and Vijay S. Pande. Journal of Computational Chemistry (2005)

SUMMARY: How do the results of peptide simulations change with slight variations to the models employed? Here we answer this question with respect to very local changes in the energetics of the polymer, demonstrating the sensitivity of simulated bulk (i.e. ensemble averaged) structural equilibrium on the parameters of the model.

TECHNICAL ABSTRACT: The kinetic and thermodynamic aspects of the helix-coil transition in polyalanine-based peptides have been studied at the ensemble level using a distributed computing network. This study builds on a previous report, which critically assessed the performance of several contemporary force fields in reproducing experimental measurements and elucidated the complex nature of helix-coil systems. Here we consider the effects of modifying backbone torsions and the scaling of noncovalent interactions. Although these elements determine the potential of mean force between atoms separated by three covalent bonds (and thus largely determine the local conformational distributions observed in simulation), we demonstrate that the interplay between these factors is both complex and force field dependent. We quantitatively assess the heliophilicity of several helix-stabilizing potentials as well as the changes in heliophilicity resulting from such modifications, which can “make or break” the accuracy of a given force field, and our findings suggests that future force field development may need to better consider effect that vary with peptide length. This report also serves as an example of the utility of distributed computing in analyzing and improving upon contemporary force fields at the level of absolute ensemble equilibrium, the next step in force field development.