Sampling and convergence in free energy calculations of protein-ligand interactions: The binding of triphenoxypyridine derivatives to factor Xa and trypsin

Villa, A., Zangi, R., Pieffet, G. and Mark, A. E. (2003) Sampling and convergence in free energy calculations of protein-ligand interactions: The binding of triphenoxypyridine derivatives to factor Xa and trypsin. Journal of Computer-aided Molecular Design, 17 10: 673-686. doi:10.1023/B:JCAM.0000017374.53591.32


Author Villa, A.
Zangi, R.
Pieffet, G.
Mark, A. E.
Title Sampling and convergence in free energy calculations of protein-ligand interactions: The binding of triphenoxypyridine derivatives to factor Xa and trypsin
Journal name Journal of Computer-aided Molecular Design   Check publisher's open access policy
ISSN 0920-654X
Publication date 2003-01-01
Sub-type Article (original research)
DOI 10.1023/B:JCAM.0000017374.53591.32
Volume 17
Issue 10
Start page 673
End page 686
Total pages 14
Place of publication Dordrecht
Publisher Kluwer Academic Publ
Language eng
Abstract The binding of a set of 10 triphenoxypyridine derivatives to two serine proteases, factor Xa and trypsin, has been used to analyze factors related to sampling and convergence in free energy calculations based on molecular dynamics simulation techniques. The inhibitors investigated were initially proposed as part of the Critical Assessment of Techniques for Free Energy Evaluation (CATFEE) project for which no experimental results nor any assessment of the predictions submitted by various groups have ever been published. The inhibitors studied represent a severe challenge for explicit free energy calculations. The mutations from one compound to another involve up to 19 atoms, the creation and annihilation of net charge and several alternate binding modes. Nevertheless, we demonstrate that it is possible to obtain highly converged results (+/-5-10 kJ/mol) even for such complex multi-atom mutations by simulating on a nanosecond time scale. This is achieved by using soft-core potentials to facilitate the creation and deletion of atoms and by a careful choice of mutation pathway. The results show that given modest computational resources, explicit free energy calculations can be successfully applied to realistic problems in drug design.
Keyword Biochemistry & Molecular Biology
Biophysics
Computer Science, Interdisciplinary Applications
Molecular-dynamics
Simulations
Inhibitors
Solvation
Complexes
Q-Index Code C1
Q-Index Status Provisional Code
Institutional Status Unknown

Document type: Journal Article
Sub-type: Article (original research)
Collections: Excellence in Research Australia (ERA) - Collection
School of Chemistry and Molecular Biosciences
 
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Created: Thu, 20 Sep 2007, 05:08:40 EST