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Role of water and steric constraints in the kinetics of cavity-ligand unbinding.
Tiwary, Pratyush; Mondal, Jagannath; Morrone, Joseph A; Berne, B J.
Afiliación
  • Tiwary P; Department of Chemistry, Columbia University, New York, NY 10027;
  • Mondal J; Department of Chemistry, Columbia University, New York, NY 10027; Tata Institute of Fundamental Research - Centre for Interdisciplinary Sciences, Hyderabad 500075, India;
  • Morrone JA; Laufer Center for Physical and Quantitative Biology, Stony Brook University, Stony Brook, NY 11794.
  • Berne BJ; Department of Chemistry, Columbia University, New York, NY 10027; bb8@columbia.edu.
Proc Natl Acad Sci U S A ; 112(39): 12015-9, 2015 Sep 29.
Article en En | MEDLINE | ID: mdl-26371312
A key factor influencing a drug's efficacy is its residence time in the binding pocket of the host protein. Using atomistic computer simulation to predict this residence time and the associated dissociation process is a desirable but extremely difficult task due to the long timescales involved. This gets further complicated by the presence of biophysical factors such as steric and solvation effects. In this work, we perform molecular dynamics (MD) simulations of the unbinding of a popular prototypical hydrophobic cavity-ligand system using a metadynamics-based approach that allows direct assessment of kinetic pathways and parameters. When constrained to move in an axial manner, the unbinding time is found to be on the order of 4,000 s. In accordance with previous studies, we find that the cavity must pass through a region of sharp wetting transition manifested by sudden and high fluctuations in solvent density. When we remove the steric constraints on ligand, the unbinding happens predominantly by an alternate pathway, where the unbinding becomes 20 times faster, and the sharp wetting transition instead becomes continuous. We validate the unbinding timescales from metadynamics through a Poisson analysis, and by comparison through detailed balance to binding timescale estimates from unbiased MD. This work demonstrates that enhanced sampling can be used to perform explicit solvent MD studies at timescales previously unattainable, to our knowledge, obtaining direct and reliable pictures of the underlying physiochemical factors including free energies and rate constants.
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Agua / Ligandos / Modelos Químicos Tipo de estudio: Prognostic_studies Idioma: En Revista: Proc Natl Acad Sci U S A Año: 2015 Tipo del documento: Article Pais de publicación: Estados Unidos
Texto completo
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Agua / Ligandos / Modelos Químicos Tipo de estudio: Prognostic_studies Idioma: En Revista: Proc Natl Acad Sci U S A Año: 2015 Tipo del documento: Article Pais de publicación: Estados Unidos