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Molecular Dynamics Simulations of Site Point Mutations in the TPR domain of Cyclophilin 40 Identify Conformational States with Distinct Dynamic and Enzymatic Properties

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Original languageEnglish
Article number145101
JournalThe Journal of Chemical Physics
Volume148
Early online date9 Apr 2018
DOIs
Publication statusE-pub ahead of print - 9 Apr 2018

Abstract

Cyclophilin 40 (Cyp40) is a member of the immunophilin family that acts as a peptidyl-prolyl-isomerase (PPIase) enzyme and binds to the heat shock protein 90 (Hsp90). Its structure comprises an N-terminal cyclophilin domain and a C-terminal TPR domain. Cyp40 is overexpressed in prostate cancer and certain T-cell lymphomas. The groove for Hsp90 binding on the TPR domain includes residues Lys227 and Lys308, referred to as the carboxylate clamp and is essential for Cyp40-Hsp90 binding. In this study the effect of two mutations; K227A and K308A; and their combinative mutant was investigated by performing a total of 5.76 µs of all-atom molecular dynamics (MD) simulations in explicit solvent. All simulations, except the K308A mutant, were found to adopt two distinct (extended or compact) conformers defined by different cyclophilin-TPR interdomain distances. The K308A mutant was only observed in the extended form which is observed in the Cyp40 X-ray structure. Thee WT, K227A and combined mutant also showed bimodal distributions. The experimental melting temperature, Tm, values of the mutants correlate with the degree of compactness with the K308A extended mutant having a marginally lower melting temperature. Another novel measure of compactness determined from the MD data; the ‘coordination shell volume’ also shows a direct correlation with Tm. The MD simulations also show an allosteric effect with the mutations in the remote TPR domain having a pronounced effect on the molecular motions of the enzymatic cyclophilin domain which helps rationalise the experimentally observed increase in enzyme activity measured for all three mutations.

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