TY - JOUR
T1 - Computational Alanine Scanning with Interaction Entropy for Protein-Ligand Binding Free Energies
AU - Liu, Xiao
AU - Peng, Long
AU - Zhou, Yifan
AU - Zhang, Youzhi
AU - Zhang, John Z.H.
N1 - Funding Information:
*J. Z. H. Zhang. E-mail: [email protected]. ORCID John Z. H. Zhang: 0000-0003-4612-1863 Author Contributions #Xiao Liu and Long Peng contributed equally to this work. Funding This work was supported by National Key R&D Program of China (Grant no. 2016YFA0501700), National Natural Science Foundation of China (Grant nos. 21433004, 91753103), Shanghai Putuo District (Grant 2014-A-02), Innovation Program of Shanghai Municipal Education Commission (201701070005E00020), and NYU Global Seed Grant. We thank the Supercomputer Center of East China Normal University for providing us computer time. Notes The authors declare no competing financial interest.
Publisher Copyright:
© 2018 American Chemical Society.
PY - 2018/3/13
Y1 - 2018/3/13
N2 - 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.
AB - 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.
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U2 - 10.1021/acs.jctc.7b01295
DO - 10.1021/acs.jctc.7b01295
M3 - Article
C2 - 29406753
AN - SCOPUS:85043975925
SN - 1549-9618
VL - 14
SP - 1772
EP - 1780
JO - Journal of chemical theory and computation
JF - Journal of chemical theory and computation
IS - 3
ER -