A Comparative Linear Interaction Energy and MM/PBSA Study on SIRT1-Ligand Binding Free Energy Calculation

Eko Aditya Rifai, Marc van Dijk, Nico P.E. Vermeulen, Arry Yanuar, Daan P. Geerke

Research output: Contribution to journalArticleResearchpeer-review

Abstract

Binding free energy (ΔGbind) computation can play an important role in prioritizing compounds to be evaluated experimentally on their affinity for target proteins, yet fast and accurate ΔGbind calculation remains an elusive task. In this study, we compare the performance of two popular end-point methods, i.e., linear interaction energy (LIE) and molecular mechanics/Poisson-Boltzmann surface area (MM/PBSA), with respect to their ability to correlate calculated binding affinities of 27 thieno[3,2-d]pyrimidine-6-carboxamide-derived sirtuin 1 (SIRT1) inhibitors with experimental data. Compared with the standard single-trajectory setup of MM/PBSA, our study elucidates that LIE allows to obtain direct ("absolute") values for SIRT1 binding free energies with lower compute requirements, while the accuracy in calculating relative values for ΔGbind is comparable (Pearson's r = 0.72 and 0.64 for LIE and MM/PBSA, respectively). We also investigate the potential of combining multiple docking poses in iterative LIE models and find that Boltzmann-like weighting of outcomes of simulations starting from different poses can retrieve appropriate binding orientations. In addition, we find that in this particular case study the LIE and MM/PBSA models can be optimized by neglecting the contributions from electrostatic and polar interactions to the ΔGbind calculations.

Original languageEnglish
Pages (from-to)4018-4033
Number of pages16
JournalJournal of Chemical Information and Modeling
Volume59
Issue number9
DOIs
Publication statusPublished - 23 Sep 2019

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Sirtuin 1
Molecular mechanics
mechanic
Free energy
Ligands
energy
interaction
Electrostatics
Trajectories
Proteins
weighting
simulation

Cite this

Rifai, Eko Aditya ; van Dijk, Marc ; Vermeulen, Nico P.E. ; Yanuar, Arry ; Geerke, Daan P. / A Comparative Linear Interaction Energy and MM/PBSA Study on SIRT1-Ligand Binding Free Energy Calculation. In: Journal of Chemical Information and Modeling. 2019 ; Vol. 59, No. 9. pp. 4018-4033.
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A Comparative Linear Interaction Energy and MM/PBSA Study on SIRT1-Ligand Binding Free Energy Calculation. / Rifai, Eko Aditya; van Dijk, Marc; Vermeulen, Nico P.E.; Yanuar, Arry; Geerke, Daan P.

In: Journal of Chemical Information and Modeling, Vol. 59, No. 9, 23.09.2019, p. 4018-4033.

Research output: Contribution to journalArticleResearchpeer-review

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