Thermodynamic Sampling of Molecular Conformations

Abstract

Torsional-space Monte Carlo simulations of flexible molecules are usually based on the assumption that all values of dihedral angles have equal probability in the absence of atomic interactions. In the present paper it is shown that this assumption is not valid. Thermodynamic sampling using dihedral angles or other internal coordinates has to account for both the correct metric in conformational space and the conformation-dependence of the moment of inertia tensor. Metric and moment of inertia terms appear as conformation-dependent factors in the partition function and are obtained by proper separation of internal and rotational degrees of freedom. The importance of both factors is discussed for a number of short peptides as well as for the folded and unfolded states of a protein. It is concluded that thermodynamic Monte Carlo simulations of protein folding that neglect these correction factors tend to underestimate the stability of the folded state.