Comparison of radii sets, entropy, QM methods, and sampling on MM-PBSA, MM-GBSA, and QM/MM-GBSA ligand binding energies of F. tularensis enoyl-ACP reductase (FabI)

Pin Chih Su, Cheng Chieh Tsai, Shahila Mehboob, Kirk Hevener, Michael E. Johnson

Research output: Contribution to journalArticle

41 Citations (Scopus)

Abstract

To validate a method for predicting the binding affinities of FabI inhibitors, three implicit solvent methods, MM-PBSA, MM-GBSA, and QM/MM-GBSA were carefully compared using 16 benzimidazole inhibitors in complex with Francisella tularensis FabI. The data suggests that the prediction results are sensitive to radii sets, GB methods, QM Hamiltonians, sampling protocols, and simulation length, if only one simulation trajectory is used for each ligand. In this case, QM/MM-GBSA using 6 ns MD simulation trajectories together with GBneck2, PM3, and the mbondi2 radii set, generate the closest agreement with experimental values (r2=0.88). However, if the three implicit solvent methods are averaged from six 1 ns MD simulations for each ligand (called "multiple independent sampling"), the prediction results are relatively insensitive to all the tested parameters. Moreover, MM/GBSA together with GBHCT and mbondi, using 600 frames extracted evenly from six 0.25 ns MD simulations, can also provide accurate prediction to experimental values (r2=0.84). Therefore, the multiple independent sampling method can be more efficient than a single, long simulation method. Since future scaffold expansions may significantly change the benzimidazole's physiochemical properties (charges, etc.) and possibly binding modes, which may affect the sensitivities of various parameters, the relatively insensitive "multiple independent sampling method" may avoid the need of an entirely new validation study. Moreover, due to large fluctuating entropy values, (QM/)MM-P(G)BSA were limited to inhibitors' relative affinity prediction, but not the absolute affinity. The developed protocol will support an ongoing benzimidazole lead optimization program.

Original languageEnglish (US)
Pages (from-to)1859-1873
Number of pages15
JournalJournal of Computational Chemistry
Volume36
Issue number25
DOIs
StatePublished - Sep 1 2015
Externally publishedYes

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Entropy Method
Binding Energy
MD Simulation
Binding energy
Oxidoreductases
Entropy
Ligands
Radius
Sampling
Inhibitor
Affine transformation
Prediction
Sampling Methods
Trajectories
Trajectory
Hamiltonians
Scaffold
Set theory
Scaffolds
Simulation Methods

All Science Journal Classification (ASJC) codes

  • Chemistry(all)
  • Computational Mathematics

Cite this

Comparison of radii sets, entropy, QM methods, and sampling on MM-PBSA, MM-GBSA, and QM/MM-GBSA ligand binding energies of F. tularensis enoyl-ACP reductase (FabI). / Su, Pin Chih; Tsai, Cheng Chieh; Mehboob, Shahila; Hevener, Kirk; Johnson, Michael E.

In: Journal of Computational Chemistry, Vol. 36, No. 25, 01.09.2015, p. 1859-1873.

Research output: Contribution to journalArticle

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