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 χ₁ of Val and Thr in proteins of known structure show distinctive features: Val side chains predominantly adopt χ₁ = 180°, whereas Thr side chains typically adopt χ₁ = 60° and 300° (i.e., χ₁ = ±60° 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.