Accurate and Rigorous Prediction of the Changes in Protein Free Energies in a Large-Scale Mutation Scan

被引:106
作者
Gapsys, Vytautas [1 ]
Michielssens, Servaas [1 ]
Seeliger, Daniel [2 ]
de Groot, Bert L. [1 ]
机构
[1] Max Planck Inst Biophys Chem, Computat Biomol Dynam Grp, Fassberg 11, D-37077 Gottingen, Germany
[2] Boehringer Ingelheim Pharma GmbH & Co KG, Identificat & Optimizat Support, Birkendorfer Str 65, D-88397 Biberach, Germany
关键词
force field; free-energy calculations; proteins; thermostability; NEUROTENSIN RECEPTOR; DIRECTED EVOLUTION;
D O I
10.1002/anie.201510054
中图分类号
O6 [化学];
学科分类号
0703 ;
摘要
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.
引用
收藏
页码:7364 / 7368
页数:5
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