Computational Alanine Scanning with Interaction Entropy for Protein-Ligand Binding Free Energies

Xiao Liu, Long Peng, Yifan Zhou, Youzhi Zhang, John Zhang

Research output: Contribution to journalArticle

Abstract

In protein-ligand binding, only a few residues contribute significantly to the ligand binding. Quantitative characterization of binding free energies of specific residues in protein-ligand binding is extremely useful in our understanding of drug resistance and rational drug design. In this paper, we present an alanine scanning approach combined with an efficient interaction entropy method to compute residue-specific protein-ligand binding free energies in protein-drug binding. In the current approach, the entropic components in the free energies of all residues binding to the ligand are explicitly computed from just a single trajectory MD simulation by using the interaction entropy method. In this approach the entropic contribution to binding free energy is determined from fluctuations of individual residue-ligand interaction energies contained in the MD trajectory. The calculated residue-specific binding free energies give relative values between those for ligand binding to the wild type protein and those to the mutants when specific results mutated to alanine. Computational study for the binding of two classes of drugs (first and second generation drugs) to target protein ALK and its mutant was performed. Important or hot spot residues with large contributions to the total binding energy are quantitatively characterized and the mutation effect for the loss of binding affinity for the first generation drug is explained. Finally, it is very interesting to note that the sum of those individual residue-specific binding free energies are in quite good agreement with the experimentally measured total binding free energies for this protein-ligand system.

Original languageEnglish (US)
Pages (from-to)1772-1780
Number of pages9
JournalJournal of Chemical Theory and Computation
Volume14
Issue number3
DOIs
StatePublished - Mar 13 2018

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alanine
Alanine
Free energy
Entropy
free energy
Ligands
entropy
proteins
Proteins
Scanning
ligands
scanning
interactions
Pharmaceutical Preparations
drugs
Trajectories
Binding energy
trajectories
mutations
affinity

ASJC Scopus subject areas

  • Computer Science Applications
  • Physical and Theoretical Chemistry

Cite this

Computational Alanine Scanning with Interaction Entropy for Protein-Ligand Binding Free Energies. / Liu, Xiao; Peng, Long; Zhou, Yifan; Zhang, Youzhi; Zhang, John.

In: Journal of Chemical Theory and Computation, Vol. 14, No. 3, 13.03.2018, p. 1772-1780.

Research output: Contribution to journalArticle

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