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. 2016 May 10;12(5):2459-70.
doi: 10.1021/acs.jctc.6b00134. Epub 2016 Apr 26.

Binding Energy Distribution Analysis Method: Hamiltonian Replica Exchange With Torsional Flattening for Binding Mode Prediction and Binding Free Energy Estimation

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Binding Energy Distribution Analysis Method: Hamiltonian Replica Exchange With Torsional Flattening for Binding Mode Prediction and Binding Free Energy Estimation

Ahmet Mentes et al. J Chem Theory Comput. .
Free PMC article

Abstract

Molecular dynamics modeling of complex biological systems is limited by finite simulation time. The simulations are often trapped close to local energy minima separated by high energy barriers. Here, we introduce Hamiltonian replica exchange (H-REMD) with torsional flattening in the Binding Energy Distribution Analysis Method (BEDAM), to reduce energy barriers along torsional degrees of freedom and accelerate sampling of intramolecular degrees of freedom relevant to protein-ligand binding. The method is tested on a standard benchmark (T4 Lysozyme/L99A/p-xylene complex) and on a library of HIV-1 integrase complexes derived from the SAMPL4 blind challenge. We applied the torsional flattening strategy to 26 of the 53 known binders to the HIV Integrase LEDGF site found to have a binding energy landscape funneled toward the crystal structure. We show that our approach samples the conformational space more efficiently than the original method without flattening when starting from a poorly docked pose with incorrect ligand dihedral angle conformations. In these unfavorable cases convergence to a binding pose within 2-3 Å from the crystallographic pose is obtained within a few nanoseconds of the Hamiltonian replica exchange simulation. We found that torsional flattening is insufficient in cases where trapping is due to factors other than torsional energy, such as the formation of incorrect intramolecular hydrogen bonds and stacking. Work is in progress to generalize the approach to handle these cases and thereby make it more widely applicable.

Figures

Figure 1
Figure 1
The structure of p-xylene (orange stick) bound to T4 Lysozyme: the Val111 side-chain gauche state shown in gray and Val111 side-chain trans state shown in red.
Figure 2
Figure 2
The distribution of △G and binding energy (BE) values from BEDAM simulations for binders vs non-binders starting from the crystallographic pose and the docked pose.
Figure 3
Figure 3
The crystal (a) and the docked (b) structures of ligand AVX38783-1-1 in the binding site; ligand in green, receptor residues within 5 Å from the ligand and hydrogen bonds between receptor-ligand shown with dashed red line. On the top, rotatable torsions of the ligand used for torsional flattening are listed.
Figure 4
Figure 4
The crystal (a) and the docked (b) structures of ligand AVX40811-0 in the binding site; ligand in green, receptor residues within 5 Å from the ligand and hydrogen bonds between receptor-ligand shown with dashed red line. On the top, rotatable torsions of the ligand used for torsional flattening are listed.
Figure 5
Figure 5
Val111 side chain dihedral angle as a function of simulation time for the final lambda values. Two figures on the top are for simulations with no flattening of side chain torsions: Initial starting conformation is gauche (a), Initial starting conformation is trans (b). Two figures on the bottom are for simulations with flattening of side chain torsions: Initial starting conformation is gauche (c), Initial starting conformation is trans (d).
Figure 6
Figure 6
All heavy atom RMSD of ligand AVX38783-1-1 (a) and AVX40811-0 (b) at λb=1 from BEDAM simulations with (blue) and without (green) torsional flattening (starting conformation is docked structure).
Figure 7
Figure 7
Binding energy of the ligand AVX38783-1-1 (a) and AVX40811-0 (b) with ligand RMSD at λb=1 from three different BEDAM simulations; green: starting conformation is docked structure without torsional flattening, red: starting conformation is crystal structure without torsional flattening, blue: starting conformation is docked structure with torsional flattening. Additionally, the RMSD between predicted pose (gray) and the validation (crystallographic) pose (green) for each ligand are given.
Figure 8
Figure 8
Distributions of the first four torsions (a, b, c, d for X1, X2, X3, X4 , respectively and also see the Figure 3 for the definition of the flattened torsions) of the ligand AVX38783-1-1 from simulations at λb = 1 with and without torsional flattening starting from the crystal and docked structures. In the standard BEDAM (with no flattening), each torsion angle shows one or two peak(s) at different locations depending on the initial ligand poses. In the BEDAM with torsional flattening calculations (in blue), simulations started with the docked ligand structure were able to sample correct ligand poses given in the crystal structures, thus it shows different peaks where we get from the standard BEDAM calculations starting with the docked and crystal structures.
Figure 9
Figure 9
a) Binding energy of AVX38789-1 and b) Binding energy + intramolecular ligand energy of AVX38789-1 with ligand RMSD at λb=l from two different BEDAM simulations; green: starting conformation is docked structure, red: starting conformation is crystal structure. c) No intramolecular ligand hydrogen bond (H-bond) formed in the initial crystal structure, d) A non-native intramolecular ligand hydrogen bond (H-bond) formed between polar hydrogen and carboxylate oxygen in the initial docked structure.

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