Journal
ANGEWANDTE CHEMIE-INTERNATIONAL EDITION
Volume 55, Issue 26, Pages 7364-7368Publisher
WILEY-V C H VERLAG GMBH
DOI: 10.1002/anie.201510054
Keywords
force field; free-energy calculations; proteins; thermostability
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Funding
- Boehringer Ingelheim Pharma GmbH
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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.
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