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A new method to model membrane protein structure based on silent amino acid substitutions
Author(s) -
Briggs John A.G.,
Torres Jaume,
Arkin Isaiah T.
Publication year - 2001
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.1102
Subject(s) - homology modeling , transmembrane domain , glycophorin , transmembrane protein , mutagenesis , computational biology , amino acid , membrane protein , protein structure , homology (biology) , biology , chemistry , genetics , biochemistry , gene , membrane , mutant , receptor , enzyme
The importance of accurately modeling membrane proteins cannot be overstated, in lieu of the difficulties in solving their structures experimentally. Often, however, modeling procedures (e.g., global searching molecular dynamics) generate several possible candidates rather then pointing to a single model. Herein we present a new approach to select among candidate models based on the general hypothesis that silent amino acid substitutions, present in variants identified from evolutionary conservation data or mutagenesis analysis, do not affect the stability of a native structure but may destabilize the non‐native structures also found. The proof of this hypothesis has been tested on the α‐helical transmembrane domains of two homodimers, human glycophorin A and human CD3‐ζ, a component of the T‐cell receptor. For both proteins, only one structure was identified using all the variants. For glycophorin A, this structure is virtually identical to the structure determined experimentally by NMR. We present a model for the transmembrane domain of CD3‐ζ that is consistent with predictions based on mutagenesis, homology modeling, and the presence of a disulfide bond. Our experiments suggest that this method allows the prediction of transmembrane domain structure based only on widely available evolutionary conservation data. Proteins 2001;44:370–375. © 2001 Wiley‐Liss, Inc.