Molecular Dynamics Simulations of a Polyalanine Octapeptide under Ewald Boundary Conditions: Influence of Artificial Periodicity on Peptide Conformation

Abstract

Ewald and related mesh methods are nowadays routinely used in explicit-solvent simulations of solvated biomolecules, although they impose an artificial periodicity in systems which are inherently nonperiodic. In the present study, we investigate the consequences of this approximation for the conformational equilibrium of a polyalanine octapeptide (with charged termini) in water. We report three explicit-solvent molecular dynamics simulations of this peptide in cubic unit cells of edges L = 2, 3, and 4 nm, using the particle−particle−particle−mesh (P 3 M) method for handling electrostatic interactions. The initial configuration of the peptide is α-helical. In the largest unit cell ( L = 4 nm), the helix unfolds quickly toward configurations with shorter end-to-end distances. By contrast, in the two smaller unit cells ( L = 2 and 3 nm), the α-helix remains stable during 2 ns. Backbone fluctuations are somewhat larger in the medium ( L = 3 nm) compared to the smallest unit cell. These differences are rationalized using a continuum electrostatics analysis of configurations from the simulations. These calculations show that the α-helical conformation is stabilized by artificial periodicity relative to any other configuration sampled during the trajectories. This artificial stabilization is larger for smaller unit cells, and is responsible for the absence of unfolding in the two smaller unit cells and the reduced backbone fluctuations in the smallest unit cell. These results suggest that artificial periodicity imposed by the use of infinite periodic (Ewald) boundary conditions in explicit-solvent simulations of biomolecules may significantly perturb the potentials of mean force for conformational equilibria, and even in some cases invert the relative stabilities of the folded and unfolded states.