Grand canonical Monte Carlo simulation of ligand - Protein binding

Matthew Clark, Frank Guarnieri, Igor Shkurko, Jeff Wiseman

Research output: Contribution to journalArticle

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A new application of the grand canonical thermodynamics ensemble to compute ligand - protein binding is described. The described method is sufficiently rapid that it is practical to compute ligand - protein binding free energies for a large number of poses over the entire protein surface, thus identifying multiple putative ligand binding sites. In addition, the method computes binding free energies for a large number of poses. The method is demonstrated by the simulation of two protein - ligand systems, thermolysin and T4 lysozyme, for which there is extensive thermodynamic and crystallographic data for the binding of small, rigid ligands. These low-molecular-weight ligands correspond to the molecular fragments used in computational fragment-based drug design. The simulations correctly identified the experimental binding poses and rank ordered the affinities of ligands in each of these systems.

Original languageEnglish
Pages (from-to)231-242
Number of pages12
JournalJournal of Chemical Information and Modeling
Issue number1
StatePublished - Jan 1 2006
Externally publishedYes


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