Multidimensional adaptive umbrella sampling: Applications to main chain and side chain peptide conformations

Abstract

A new adaptive umbrella sampling technique for molecular dynamics simulations is described. The high efficiency of the technique renders multidimensional adaptive umbrella sampling possible and thereby enables uniform sampling of the conformational space spanned by several degrees of freedom. The efficiency is achieved by using the weighted histogram analysis method to combine the results from different simulations, by a suitable extrapolation scheme to define the umbrella potential for regions that have not been sampled, and by a criterion to identify simulations during which the system was not in equilibrium. The technique is applied to two test systems, the alanine dipeptide and the threonine dipeptide, to sample the configurational space spanned by one or two dihedral angles. The umbrella potentials applied at the end of each adaptive umbrella sampling run are equal to the negative of the corresponding potentials of mean force. The trajectories obtained in the simulations can be used to calculate dynamical variables that are of interest. An example is the distribution of the distance between the HN and the Hβ proton that can be important for the interpretation of NMR experiments. Factors influencing the accuracy of the calculated quantities are discussed. © 1997 John Wiley & Sons, Inc. J Comput Chem 18: 1450–1462, 1997