Towards Temperature Dependent Coarse-grained Potential of Side-chain Interactions for Protein Folding Simulations

Based on the results of our recent work on the determination of the potentials of mean force of pairs of models of amino-acid side chains in water, in this work we make an attempt at introducing temperature-dependent side chain – side chain interaction potentials in our coarse-grained UNRES energy function. For hydrophobic pairs as well as oppositely-charged pairs, two functional forms are introduced, one of which implies a linear dependence of the free energy of interactions on temperature and the other one a hyperbolic-tangent dependence. The free energy of the interactions of other pairs is assumed to be independent of temperature. With the example of the N-terminal part of the B-domain of staphylococcal protein A, we demonstrate that, with this temperature dependence, the radius of gyration and the root-mean-square deviation from the native structure grow less steeply with temperature and the heat-capacity peak is lower than that obtained with temperature-independent side chain – side chain potentials. This demonstrates that ignoring the increase of the strength of hydrophobic interactions with increasing temperature in coarse-grained force fields is likely to result in grossly wrong predictions of the thermodynamics of folding and of the process of thermal unfolding made with such force fields.