Exploring the conformational space for protein folding with sequential Monte Carlo

Abstract

Computational methods for protein structure prediction from amino acid sequence are of vital importance in modern applications, for example protein design in biomedicine. Efficient sampling of conformations according to a given energy function remains a bottleneck, yet is a vital step for energy-based structure prediction methods. While the Protein Data Bank of experimentally determined 3-D protein structures has steadily increased in size, structure predictions for new proteins tend to be unreliable in the amino acid segments where there is low sequence similarity with known structures. In this paper we introduce a new method for building such segments of protein structures, inspired by sequential Monte Carlo methods. We apply our method to examples of real 3-D structure predictions and demonstrate its promise for improving low confidence segments. We also provide applications to the prediction of reconstructed segments in known structures, and to the assessment of energy function accuracy. We find that our method is able to produce conformations that have both low energies and good coverage of the conformational space and hence can be a useful tool for protein design and structure prediction.