Computational Model to Predict Folding Stability of FKBP

Abstract

The folded structure of a protein is stabilized by a variety of interactions including hydrophobic and electrostatic interactions. A computational method to predict the effects of mutations on folding stability of FKBP is presented here, and the predictions are compared with experimental data from our lab. The method improves upon our previous studies [1-3] and incorporates conformational sampling, generated by a molecular dynamic simulation of the wild-type protein, in the calculations. We apply a clustering method to remove apparent outliers in the sampled conformations, thereby increasing the robustness of the calculation results. For 16 point mutations involving charged or polar side chains, the root-mean-squared deviation between electrostatics-only prediction and experiment is 0.9 kcal/mol. Further improvement is sought by including contributions of van der Waals and hydrophobic interactions. Our combined computational and experimental study will provide insight on the physical basis of protein folding stability.[1] Zhou, H.-X. and F. Dong (2003) Electrostatic contributions to the stability of a Thermophilic Cold Shock Protein. Biophys. J. 84: 2216-2222.[2] Dong, F. and H.-X. Zhou (2002) Electrostatic contributions to T4 lysozyme stability: solvent-exposed charges versus semi-buried salt bridges. Biophys. J. 83: 1341-1347.[3] Zhou, H.-X. (2002) A Gaussian-chain model for treating residual charge-charge interactions in the unfolded state of proteins. Proc. Natl. Acad. Sci. USA 99: 3569-3574.