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Evaluation of conformational changes in diabetes‐associated mutation in insulin a chain: A molecular dynamics study
Author(s) -
Kim Yong Hwan,
Kastner Kevin,
AbdulWahid Badi,
Izaguirre Jesús A.
Publication year - 2015
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.24759
Subject(s) - proinsulin , mutant , mutation , chemistry , protein folding , folding (dsp implementation) , insulin , cysteine , protein structure , gene , biochemistry , biology , endocrinology , enzyme , engineering , electrical engineering
Insulin plays a central role in the regulation of metabolism in humans. Mutations in the insulin gene can impair the folding of its precursor protein, proinsulin, and cause permanent neonatal‐onset diabetes mellitus known as Mutant INS‐gene induced Diabetes of Youth (MIDY) with insulin deficiency. To gain insights into the molecular basis of this diabetes‐associated mutation, we perform molecular dynamics simulations in wild‐type and mutant (Cys A7 to Tyr or C(A7)Y) insulin A chain in aqueous solutions. The C(A7)Y mutation is one of the identified mutations that impairs the protein folding by substituting the cysteine residue which is required for the disulfide bond formation. A comparative analysis reveals structural differences between the wild‐type and the mutant conformations. The analyzed mutant insulin A chain forms a metastable state with major effects on its N‐terminal region. This suggests that MIDY mutant involves formation of a partially folded intermediate with conformational change in N‐terminal region in A chain that generates flexible N‐terminal domain. This may lead to the abnormal interactions with other proinsulins in the aggregation process. Proteins 2015; 83:662–669. © 2015 Wiley Periodicals, Inc.