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Probing the conformational space available to inhibitors in the thermolysin active site using Monte Carlo/energy minimization techniques
Author(s) -
Guida Wayne C.,
Bohacek Regine S.,
Erion Mark D.
Publication year - 1992
Publication title -
journal of computational chemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.907
H-Index - 188
eISSN - 1096-987X
pISSN - 0192-8651
DOI - 10.1002/jcc.540130213
Subject(s) - thermolysin , conformational isomerism , solvation , monte carlo method , chemistry , energy minimization , computational chemistry , accessible surface area , force field (fiction) , active site , computation , potential energy surface , potential energy , molecular mechanics , ab initio , molecular dynamics , molecule , physics , atomic physics , enzyme , computer science , quantum mechanics , algorithm , mathematics , organic chemistry , statistics , trypsin
Abstract The conformational space available to four inhibitors of the bacterial enzyme thermolysin has been searched in the enzyme binding site using a method that combines Monte Carlo type techniques with energy minimization for exploration of the conformational potential energy hypersurface. Molecular mechanics methodology using the AMBER force field was employed for computation of the molecular energetics. Solvation energies were also included in the calculations by employing a technique that estimates hydration energies based on the exposed solvent accessible surface area for each atom of the inhibitor and active site. It was found that in each case, the crystallographically observed conformation was among the low energy conformers discovered. In fact, in three of the calculations it was the lowest energy conformation. The methodology described in this article is expected to be quite useful for studies involving computer aided design and evaluation of enzyme inhibitors.