Exploiting molecular dynamics in Nested Sampling simulations of small peptides

Nested Sampling (NS) is a parameter space sampling algorithm which can be used for sampling the equilibrium thermodynamics of atomistic systems. NS has previously been used to explore the potential energy surface of a coarse-grained protein model and has significantly outperformed parallel tempering when calculating heat capacity curves of Lennard-Jones clusters. The original NS algorithm uses Monte Carlo (MC) moves; however, a variant, Galilean NS, has recently been introduced which allows NS to be incorporated into a molecular dynamics framework, so NS can be used for systems which lack efficient prescribed MC moves. In this work we demonstrate the applicability of Galilean NS to atomistic systems. We present an implementation of Galilean NS using the Amber molecular dynamics package and demonstrate its viability by sampling alanine dipeptide, both in vacuo and implicit solvent. Unlike previous studies of this system, we present the heat capacity curves of alanine dipeptide, whose calculation provides a stringent test for sampling algorithms. We also compare our results with those calculated using replica exchange molecular dynamics (REMD) and find good agreement. We show the computational effort required for accurate heat capacity estimation for small peptides. We also calculate the alanine dipeptide Ramachandran free energy surface for a range of temperatures and use it to compare the results using the latest Amber force field with previous theoretical and experimental results.