The Power of Hard-Sphere Models: Explaining Side-Chain Dihedral Angle Distributions of Thr and Val

The energy functions used to predict protein structures typically include both molecular-mechanics and knowledge-based terms. In contrast, our approach is to develop robust physics-and geometry-based methods. Here, we investigate to what extent simple hard-sphere models can be used to predict side-chain conformations. The distributions of the side-chain dihedral angle chi(1) of Val and Thr in proteins of known structure show distinctive features: Val side chains predominantly adopt chi(1) = 180 degrees, whereas Thr side chains typically adopt chi(1) = 60 degrees and 300 degrees (i.e., chi(1) = +/- 60 degrees or g- and g(+) configurations). Several hypotheses have been proposed to explain these differences, including interresidue steric clashes and hydrogen-bonding interactions. In contrast, we show that the observed side-chain dihedral angle distributions for both Val and Thr can be explained using only local steric interactions in a dipeptide mimetic. Our results emphasize the power of simple physical approaches and their importance for future advances in protein engineering and design.