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Specificity of glycosaminoglycan‐protein interactions: the role of desolvation (1007.5)
Author(s) -
Sarkar Aurijit,
Desai Umesh
Publication year - 2014
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.28.1_supplement.1007.5
Subject(s) - chemistry , hydrogen bond , serpin , glycosaminoglycan , antithrombin , residue (chemistry) , mutagenesis , biochemistry , heparin , stereochemistry , molecule , mutation , gene , organic chemistry
Why do most glycosaminoglycan (GAG)‐protein interactions lack specificity? We hypothesized that desolvation of highly charged groups, which is highly unfavorable, plays an as‐yet‐unrecognized dominant role. We performed molecular dynamics (MD) simulations of water binding to antithrombin (AT) and thrombin (T), two prototypic ‘specific’ and ‘non‐specific’ GAG‐binding proteins respectively, to parse the role of desolvation energy (DE). The DE for Arg/Lys sidechains was a substantial ~4.5 kcal/mol, which counteracts enthalpic gains during hydrogen‐bond formation with GAG sulfates. This DE was irrespective of the location ‐ within the heparin‐binding site (HBS) or elsewhere ‐ on either protein, suggesting that hydrogen‐bonding by Arg/Lys residues with GAG sulfates does not explain the interaction specificity. However, DE for selected uncharged sidechain‐ and/or backbone‐ donors may play a dominant role. Specifically, Asn45 of AT contributes singularly to GAG recognition with a much‐reduced DE, while no such equivalent uncharged residue exists for T. These results find support in mutagenesis and crystallography studies reported in literature. The key finding that GAG specificity for proteins arises from hydrogen‐bonding with a select group of uncharged donors due to lower DE penalty is being extended to the serpin family of proteins. Grant Funding Source : Supported by NIH grants R01 HL090586 and P01 HL107152 to URD, and NCCR grant S10 RR027411 to VCU.