Binding dynamics of two water molecules constrained within the scytalone dehydratase binding pocket

Bioorganic and Medicinal Chemistry Letters

Volumn 10, Issue 1, 2000, Pages 23-26

  Jordan, Douglas B ^a   Basarab, Gregory S ^a  

^a DUPONT COMPANY   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

HYDROLASE INHIBITOR; HYDROLYASE; WATER;

ARTICLE; BINDING AFFINITY; CATALYSIS; CHEMICAL BINDING; CHEMICAL STRUCTURE; ENZYME ACTIVE SITE; HYDROGEN BOND; MOLECULAR DYNAMICS; MOLECULAR STABILITY; MUTATION;

BINDING SITES; COMPUTER SIMULATION; DRUG DESIGN; ENZYME INHIBITORS; HYDRO-LYASES; KINETICS; MODELS, CHEMICAL; MUTAGENESIS, SITE-DIRECTED; SALICYLAMIDES; THERMODYNAMICS; WATER;

EID: 0034598361     PISSN: 0960894X     EISSN: None     Source Type: Journal    
DOI: 10.1016/S0960-894X(99)00586-7     Document Type: Article

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13. 7) was modified by replacing the bromophenyl group with a methyl group. Valences of the protein, water molecules and inhibitor were satisfied with hydrogen atoms. Charges for all atoms were calculated using the Gasteiger-Marsili algorithm. The internal strain of a 10 Å shell around the inhibitor was relaxed using the Tripos force field with a Powell gradient to a convergence of 0.05 kcal/mol. For the molecular dynamics simulation, the modified inhibitor and the two waters were constrained by the protein that was held as an immovable aggregate. Using 1 fs time steps, the system was heated from 0 to 300 K by 50 K steps every ps and equilibrated at 300 K for a period of 200 ps. Structures were stored every ps. The Tripos force field was used for the simulation with the Verlet method of integration and the SHAKE method to hold hydrogen/heteroatom bonds at a fixed length. Non-bonded interactions were updated every 25 fs. The van der Waals energy and electrostatic terms were switched off at distances greater than 8 Å. A dielectric constant of 1.0 was used.
14. Compound 2 was prepared as described in ref 8.
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