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Digitale Medien

Fitting an inhibitor into the active site of thermolysin: A molecular dynamics case study (1996)

Wasserman, Zelda R. ; Hodge, C. Nicholas

New York, NY : Wiley-Blackwell

Proteins: Structure, Function, and Genetics 24 (1996), S. 227-237

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ISSN: 0887-3585

Schlagwort(e): computer simulation ; metalloenzymes ; protein/ligand interactions ; rational drug design ; substrate docking ; Chemistry ; Biochemistry and Biotechnology

Quelle: Wiley InterScience Backfile Collection 1832-2000

Thema: Medizin

Notizen: We used molecular dynamics computer simulation to “fly” a small flexible ligand, L-leucine hydroxamic acid, into the active site of thermolysin. The potential, which imposed no constraints between protein and ligand, produced conformations close to the crystallographically determined one. The calculations made use of the combined molecular mechanics/grid method of Luty et al. (J. Comp. Chem. 16:454-464, 1995), in which atoms of the active site are free to move whereas the rest of the protein, assumed to be rigid, is represented as points of a grid, and which also includes an implicit solvation model. The method is sufficiently fast that large sets of simulations could be carried out, enabling statistical sampling and exploration of the effect of initial position and conformation of the ligand on the probability of successful docking. In a charged catalytic Glu/uncharged ligand regime, when the initial position of the ligand was determined by random translations and rotations that kept the center of mass within 8.0 Å of the crystal one, none of the 20 runs placed the ligand correctly. In a second set with uncharged Glu and zwitterionic ligand, 3 of 24 similarly placed random structures flew the ligand in successfully. In a third set with the same protonation scheme as the second the starting positions had randomly determined conformations but kept the hydroxyamate oxygens within 4.0 Å of the zinc; in this case 22 of 25 runs reoriented correctly. A diverse set of energetic, structural, and dynamic criteria was used for evaluation of the calculations. The results indicate the method to be a promising tool for the rational drug design process.

Zusätzliches Material: 8 Ill.

Materialart: Digitale Medien

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Digitale Medien

A molecular mechanics/grid method for evaluation of ligand-receptor interactions (1995)

Luty, Brock A. ; Wasserman, Zelda R. ; Stouten, Pieter F. W. ; [weitere]

New York, NY [u.a.] : Wiley-Blackwell

Journal of Computational Chemistry 16 (1995), S. 454-464

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ISSN: 0192-8651

Schlagwort(e): Computational Chemistry and Molecular Modeling ; Biochemistry

Quelle: Wiley InterScience Backfile Collection 1832-2000

Thema: Chemie und Pharmazie , Informatik

Notizen: We present a computational method for prediction of the conformation of a ligand when bound to a macromolecular receptor. The method is intended for use in systems in which the approximate location of the binding site is known and no large-scale rearrangements of the receptor are expected upon formation of the complex. The ligand is initially placed in the vicinity of the binding site and the atomic motions of the ligand and binding site are explicitly simulated, with solvent represented by an implicit solvation model and using a grid representation for the bulk of the receptor protein. These two approximations make the method computationally efficient and yet maintain accuracy close to that of an all-atom calculation. For the benzamidine/trypsin system, we ran 100 independent simulations, in many of which the ligand settled into the low-energy conformation observed in the crystal structure of the complex. The energy of these conformations was lower than and well-separated from that of others sampled. Extensions of this method are also discussed. © 1995 by John Wiley & Sons, Inc.

Zusätzliches Material: 4 Ill.

Materialart: Digitale Medien

URL: http://dx.doi.org/10.1002/jcc.540160409

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