Peptide Dynamics and Metadynamics: Leveraging Enhanced Sampling Molecular Dynamics to Robustly Model Long-Timescale Transitions.

Abstract

Molecular dynamics simulations can in theory reveal the thermodynamics and kinetics of peptide conformational transitions at atomic-level resolution. However, even with modern computing power, they are limited in the timescales they can sample, which is especially problematic for peptides that are fully or partially disordered. Here, we discuss how the enhanced sampling methods accelerated molecular dynamics (aMD) and metadynamics can be leveraged in a complementary fashion to quickly explore conformational space and then robustly quantify the underlying free energy landscape. We apply these methods to two peptides that have an intrinsically disordered nature, the histone H3 and H4 N-terminal tails, and use metadynamics to compute the free energy landscape along collective variables discerned from aMD simulations. Results show that these peptides are largely disordered, with a slight preference for α-helical structures.