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Possible ligand release pathway of dipeptidyl peptidase IV investigated by molecular dynamics simulations
Author(s) -
Li Cui,
Shen Jie,
Li Weihua,
Lu Chunhua,
Liu Guixia,
Tang Yun
Publication year - 2011
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.23004
Subject(s) - active site , molecular dynamics , chemistry , dipeptidyl peptidase 4 , dipeptidyl peptidase , ligand (biochemistry) , binding site , biophysics , biochemistry , biology , enzyme , diabetes mellitus , receptor , computational chemistry , type 2 diabetes , endocrinology
Dipeptidyl peptidase IV (DPP4) is an important target for the treatment of Type II diabetes mellitus. The crystal structure of DPP4 demonstrates that there are two possible pathways to the active site, a side opening and a β propeller opening. However, it still lacks quantitative evidence to illustrate which pathway is more favorable for inhibitor to enter into or release from the active site. In this study, conventional and steered molecular dynamics simulations were performed to explore the details of inhibitor Q448 release from the active site of DPP4 via the two potential pathways. The comparisons of force and work together with potentials of mean force results suggested that the side opening might be more favorable for the inhibitor to pass through. Moreover, Glu205‐Glu206 and Phe357 were recognized as two “key residues” in the active site for inhibitor binding. Accordingly, suggestions for further inhibitor design wereprovided. Proteins 2011; © 2011 Wiley‐Liss, Inc.