The prediction of mutation-induced free-energy changes in protein thermostability or protein–protein binding is of particular interest in the fields of protein design, biotechnology, and bioengineering. Herein, we achieve remarkable accuracy in a scan of 762 mutations estimating changes in protein thermostability based on the first principles of statistical mechanics. The remaining error in the free-energy estimates appears to be due to three sources in approximately equal parts, namely sampling, force-field inaccuracies, and experimental uncertainty. We propose a consensus force-field approach, which, together with an increased sampling time, leads to a free-energy prediction accuracy that matches those reached in experiments. This versatile approach enables accurate free-energy estimates for diverse proteins, including the prediction of changes in the melting temperature of the membrane protein neurotensin receptor 1.
Carsten Kutzner; Szilárd Páll; Martin Fechner; Ansgar Esztermann; Bert L. de Groot; Helmut Grubmüller (2016):
Accurate and Rigorous Prediction of the Changes in Protein Free Energies in a Large-Scale Mutation Scan.
Angewandte Chemie International Edition 55(26)