Computational fragment-based binding site identification by ligand competitive saturation.

Printer-friendly versionPrinter-friendly versionPDF versionPDF version
TitleComputational fragment-based binding site identification by ligand competitive saturation.
Publication TypeJournal Article
Year of Publication2009
AuthorsGuvench, O, Mackerell, AD
JournalPLoS Comput Biol
Volume5
Issue7
Paginatione1000435
Date Published2009 Jul
ISSN1553-7358
KeywordsBinding Sites, Binding, Competitive, Carbon, Computational Biology, Computer Simulation, Crystallography, X-Ray, DNA-Binding Proteins, Drug Discovery, Hydrogen Bonding, Ligands, Models, Molecular, Peptide Fragments, Protein Binding, Protein Conformation, Proto-Oncogene Proteins c-bcl-6, Reproducibility of Results, Thermodynamics
Abstract

Fragment-based drug discovery using NMR and x-ray crystallographic methods has proven utility but also non-trivial time, materials, and labor costs. Current computational fragment-based approaches circumvent these issues but suffer from limited representations of protein flexibility and solvation effects, leading to difficulties with rigorous ranking of fragment affinities. To overcome these limitations we describe an explicit solvent all-atom molecular dynamics methodology (SILCS: Site Identification by Ligand Competitive Saturation) that uses small aliphatic and aromatic molecules plus water molecules to map the affinity pattern of a protein for hydrophobic groups, aromatic groups, hydrogen bond donors, and hydrogen bond acceptors. By simultaneously incorporating ligands representative of all these functionalities, the method is an in silico free energy-based competition assay that generates three-dimensional probability maps of fragment binding (FragMaps) indicating favorable fragment:protein interactions. Applied to the two-fold symmetric oncoprotein BCL-6, the SILCS method yields two-fold symmetric FragMaps that recapitulate the crystallographic binding modes of the SMRT and BCOR peptides. These FragMaps account both for important sequence and structure differences in the C-terminal halves of the two peptides and also the high mobility of the BCL-6 His116 sidechain in the peptide-binding groove. Such SILCS FragMaps can be used to qualitatively inform the design of small-molecule inhibitors or as scoring grids for high-throughput in silico docking that incorporate both an atomic-level description of solvation and protein flexibility.

DOI10.1371/journal.pcbi.1000435
Alternate JournalPLoS Comput. Biol.
PubMed ID19593374
PubMed Central IDPMC2700966
Grant ListGM51501 / GM / NIGMS NIH HHS / United States
R01 CA107331 / CA / NCI NIH HHS / United States
F32CA1197712 / CA / NCI NIH HHS / United States
CA107331 / CA / NCI NIH HHS / United States
CA120215 / CA / NCI NIH HHS / United States
R01 CA120215 / CA / NCI NIH HHS / United States
R01 GM051501 / GM / NIGMS NIH HHS / United States
R29 GM051501 / GM / NIGMS NIH HHS / United States