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Prediction of protein mutation effects based on dehydration and hydrogen bonding – A large‐scale study
Author(s) -
Schomburg Karen T.,
Nittinger Eva,
Meyder Agnes,
Bietz Stefan,
Schneider Nadine,
Lange Gudrun,
Klein Robert,
Rarey Matthias
Publication year - 2017
Publication title -
proteins: structure, function, and bioinformatics
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.699
H-Index - 191
eISSN - 1097-0134
pISSN - 0887-3585
DOI - 10.1002/prot.25315
Subject(s) - mutagenesis , side chain , mutation , hydrogen bond , point mutation , chemistry , protein structure , protein stability , protein structure prediction , computational biology , molecule , biochemistry , biology , gene , organic chemistry , polymer
Reliable computational prediction of protein side chain conformations and the energetic impact of amino acid mutations are the key aspects for the optimization of biotechnologically relevant enzymatic reactions using structure‐based design. By improving the protein stability, higher yields can be achieved. In addition, tuning the substrate selectivity of an enzymatic reaction by directed mutagenesis can lead to higher turnover rates. This work presents a novel approach to predict the conformation of a side chain mutation along with the energetic effect on the protein structure. The HYDE scoring concept applied here describes the molecular interactions primarily by evaluating the effect of dehydration and hydrogen bonding on molecular structures in aqueous solution. Here, we evaluate its capability of side‐chain conformation prediction in classic remutation experiments. Furthermore, we present a new data set for evaluating “cross‐mutations,” a new experiment that resembles real‐world application scenarios more closely. This data set consists of protein pairs with up to five point mutations. Thus, structural changes are attributed to point mutations only. In the cross‐mutation experiment, the original protein structure is mutated with the aim to predict the structure of the side chain as in the paired mutated structure. The comparison of side chain conformation prediction (“remutation”) showed that the performance of HYDE protein is qualitatively comparable to state‐of‐the art methods. The ability of HYDE protein to predict the energetic effect of a mutation is evaluated in the third experiment. Herein, the effect on protein stability is predicted correctly in 70% of the evaluated cases. Proteins 2017; 85:1550–1566. © 2017 Wiley Periodicals, Inc.