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The Binding Mechanism of Epolactaene to Hsp60 Unveiled by in Silico Modelling
Author(s) -
Spinello Angelo,
Barone Giampaolo,
Cappello Francesco,
Pace Andrea,
Buscemi Silvestre,
Palumbo Piccionello Antonio
Publication year - 2016
Publication title -
chemistryselect
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.437
H-Index - 34
ISSN - 2365-6549
DOI - 10.1002/slct.201600125
Subject(s) - hsp60 , biophysics , chemistry , chaperone (clinical) , folding (dsp implementation) , molecular dynamics , covalent bond , binding site , crystallography , heat shock protein , hsp70 , biochemistry , biology , computational chemistry , medicine , organic chemistry , pathology , electrical engineering , gene , engineering
Molecular Dynamics (MD) simulations and DFT/MM calculations were performed in order to rationalize available experimental results and to provide structural details on the binding mechanism of Epolactaene ( EPO ) to the 60 KDa Heat Shock Protein (Hsp60). The available crystal structure of Hsp60 represents the last step of the chaperone folding cycle, while the Hsp60‐ EPO complex was obtained by using a homology model of Hsp60, in order to simulate a state related to the beginning of the folding cycle (Rs1). The results of MD simulations point out that EPO shows the highest binding affinity for the empty ATP binding site. The presence of ATP opens a channel that allows the entrance of both EPO diastereoisomers. However, only ( 15S)‐EPO possesses a suitable orientation to bind its target, Cys442. A DFT/MM study was performed to investigate the structure of EPO attached through a C−S covalent bond and to estimate the binding free energy of such reaction. Interestingly, the MD simulation of Hsp60‐ EPO shows that the covalent bond between EPO and Cys442 hinders the conformational change leading to the R‐open structure, which is involved in the formation of the Hsp60/Hsp10 complex, essential for the known chaperone activity of Hsp60.