| Computational Mutagenesis in Analysis of Protein Stability and Function: Effects of Hydration |
Gregory M. Reck, Majid Masso and Iosif I. Vaisman
Department of Bioinformatics and Computational Biology, George Mason University, USA |
| Accurate predictive models for the impact of amino acid residue substitutions on protein stability provide important insights into protein structure and function. Such models are also valuable for the design and engineering of new proteins. Previously described methods have utilized properties of protein sequence or structure to predict the free energy change of mutants through the application of either computational energy-based approaches or machine learning techniques. However, accuracy associated with applying these methods separately is frequently far from optimal. We detail a computational mutagenesis technique based on a four-body, knowledge-based, statistical contact potential defined by Delaunay tessellation of amino acid residue locations only or with the inclusion of the locations of hypothetical water positions surrounding the protein. For any mutation due to a single amino acid replacement in a protein, the method provides an empirical normalized measure of the ensuing environmental perturbation occurring at every residue position. The residue environment based predictors of stability change are evaluated by applying machine learning tools to large training sets of mutants derived from diverse proteins that have been experimentally studied and described. Predictive models based on our combined approach for unhydrated and hydrated proteins are in many cases significantly outperform other existing models. |
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