Role of water in ligand binding to maltose-binding protein: insight from a new docking protocol based on the 3D-RISM-KH molecular theory of solvation

J Chem Inf Model. 2015 Feb 23;55(2):317-28. doi: 10.1021/ci500520q. Epub 2015 Jan 26.

Abstract

Maltose-binding protein is a periplasmic binding protein responsible for transport of maltooligosaccarides through the periplasmic space of Gram-negative bacteria, as a part of the ABC transport system. The molecular mechanisms of the initial ligand binding and induced large scale motion of the protein's domains still remain elusive. In this study, we use a new docking protocol that combines a recently proposed explicit water placement algorithm based on the 3D-RISM-KH molecular theory of solvation and conventional docking software (AutoDock Vina) to explain the mechanisms of maltotriose binding to the apo-open state of a maltose-binding protein. We confirm the predictions of previous NMR spectroscopic experiments on binding modes of the ligand. We provide the molecular details on the binding mode that was not previously observed in the X-ray experiments. We show that this mode, which is defined by the fine balance between the protein-ligand direct interactions and solvation effects, can trigger the protein's domain motion resulting in the holo-closed structure of the maltose-binding protein with the maltotriose ligand in excellent agreement with the experimental data. We also discuss the role of water in blocking unfavorable binding sites and water-mediated interactions contributing to the stability of observable binding modes of maltotriose.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Algorithms
  • Bacteria / chemistry
  • Bacteria / metabolism
  • Binding Sites
  • Binding, Competitive
  • Ligands
  • Magnetic Resonance Spectroscopy
  • Maltose-Binding Proteins / chemistry*
  • Models, Molecular
  • Molecular Docking Simulation / methods*
  • Protein Conformation
  • Solvents
  • Water / chemistry*

Substances

  • Ligands
  • Maltose-Binding Proteins
  • Solvents
  • Water