Excluded Volume in Protein Sidechain Packing

Abstract

To examine the relationship between sidechain geometry and sidechain packing, we use an all-atom Monte Carlo simulation to sample the large space of sidechain conformations. We study three models of excluded volume and use umbrella sampling to effectively explore the entire space. We find that while excluded volume constraints reduce the size of conformational space by many orders of magnitude, the number of allowed conformations is still large. An average repacked conformation has 20% of its chi angles in a non-native state. Interestingly, well-packed conformations, with up to 50% non-native chi's exist. Entropy is distributed non-uniformly over positions, and we partially explain the observed distribution using rotamer probabilities derived from the pdb database. In spite of our finding that 65% of the native rotamers and 85% of chi 1 angles can be correctly predicted on the basis of excluded volume only, 95% of positions can accomodate more than 1 rotamer in simulation. We estimate that in order to quench the sidechain entropy observed in the presence of excluded volume interactions, other interactions (hydrophobic, polar, electrostatic) must provide an additional stabilization of at least 0.6 kT per residue in order to single out the native state.