Spatial analysis and quantification of the thermodynamic driving forces in protein-ligand binding: binding site variability.

Printer-friendly versionPrinter-friendly versionPDF versionPDF version
TitleSpatial analysis and quantification of the thermodynamic driving forces in protein-ligand binding: binding site variability.
Publication TypeJournal Article
Year of Publication2015
AuthorsE Raman, P, Mackerell, AD
JournalJ Am Chem Soc
Volume137
Issue7
Pagination2608-21
Date Published2015 Feb 25
ISSN1520-5126
KeywordsBinding Sites, Entropy, Factor Xa, Ligands, Methanol, Molecular Dynamics Simulation, p38 Mitogen-Activated Protein Kinases, Propane, Protein Binding, Protein Conformation, Solvents, Water
Abstract

The thermodynamic driving forces behind small molecule-protein binding are still not well-understood, including the variability of those forces associated with different types of ligands in different binding pockets. To better understand these phenomena we calculate spatially resolved thermodynamic contributions of the different molecular degrees of freedom for the binding of propane and methanol to multiple pockets on the proteins Factor Xa and p38 MAP kinase. Binding thermodynamics are computed using a statistical thermodynamics based end-point method applied on a canonical ensemble comprising the protein-ligand complexes and the corresponding free states in an explicit solvent environment. Energetic and entropic contributions of water and ligand degrees of freedom computed from the configurational ensemble provide an unprecedented level of detail into the mechanisms of binding. Direct protein-ligand interaction energies play a significant role in both nonpolar and polar binding, which is comparable to water reorganization energy. Loss of interactions with water upon binding strongly compensates these contributions leading to relatively small binding enthalpies. For both solutes, the entropy of water reorganization is found to favor binding in agreement with the classical view of the "hydrophobic effect". Depending on the specifics of the binding pocket, both energy-entropy compensation and reinforcement mechanisms are observed. It is notable to have the ability to visualize the spatial distribution of the thermodynamic contributions to binding at atomic resolution showing significant differences in the thermodynamic contributions of water to the binding of propane versus methanol.

DOI10.1021/ja512054f
Alternate JournalJ. Am. Chem. Soc.
PubMed ID25625202
PubMed Central IDPMC4342289
Grant ListR01 GM070855 / GM / NIGMS NIH HHS / United States
GM051501 / GM / NIGMS NIH HHS / United States
R01 CA107331 / CA / NCI NIH HHS / United States
GM070855 / GM / NIGMS NIH HHS / United States
CA107331 / CA / NCI NIH HHS / United States
R01 GM051501 / GM / NIGMS NIH HHS / United States
R29 GM051501 / GM / NIGMS NIH HHS / United States