Energy-Driven Undocking (EDU-HREM) in Solute Tempering Replica Exchange Simulations

Abstract

We present a new computational strategy for calculating the absolute binding free energy for protein ligand association in the context of atomistic simulation in explicit solvent. The method is based on an appropriate definition of a solute tempering scheme enforced via Hamilton replica exchange method (HREM). The definition of "solute" includes both the ligand and the active site, with the remainder of the systems defined as "solvent". The hydrophilicity of the solute and the solute torsional plus nonbonded intrasolute interactions are increased and decreased, respectively, along the replica progression, thus favoring the extrusion of the drug form the active site in the scaled states of the generalized ensemble. The proposed technique, named "Energy Driven Undocking" (EDU-HREM), completely bypasses the need for defining and/or identifying the relevant reaction coordinates in a ligand receptor interactions and allows the calculation of the absolute binding free energy in one single generalized simulation of the drug-receptor system. The methodology is applied, with encouraging results, to the calculation of the absolute binding free energy of some FK506-related ligands of the peptidyl prolyl cis-trans isomerase protein (FKBP12) with known dissociation constants. Aspects of the binding/inhibition mechanism in FKBP12 are also analyzed and discussed.

Hybrid MPI/OpenMP Implementation of the ORAC Molecular Dynamics Program for Generalized Ensemble and Fast Switching Alchemical Simulations

“…See the Supporting Information for technical details on the simulation setup. An OpenMP/MPI application of the solvated IK682−TACE complex on an HPC facility could be used, for example, for an H-REM simulation, with scaling of the binding site region only, 20,21 in order to efficiently sample the fully coupled bound state; or for the production of FS-DAM independent trajectories (vide inf ra) aimed at determining the binding affinity of the ligand via the associated NE work distribution. 16 In the first instance, pilot tests for this kind of simulation have been done for a fixed slot of 1024 cores (64 compute nodes), using a total of OpenMP and MPI threads equal to the number of cores (i.e., using a single HWT per core).…”

Assessment of a Single Decoupling Alchemical Approach for the Calculation of the Absolute Binding Free Energies of Protein-Peptide Complexes

“…Cases, such as this, of slow convergence due to slow intramolecular conformational equilibration can not be easily addressed by conventional conformational sampling acceleration methods based, for example, on Hamiltonian replica exchange on the alchemical variable as done here. Some success has been gained with biasing potentials targeting specific degrees of freedom (Ensing et al, 2006 ; Kim et al, 2010 ; Procacci et al, 2013 ; Cavalli et al, 2014 ), such as dihedral angles (Wang et al, 2012 ; Lindert et al, 2013 ). We have not attempted, in this work, to obtain a converged estimate of the relative population of the two binding modes of the linear peptide using these methods.…”

SAMPL6 host–guest blind predictions using a non equilibrium alchemical approach

“…In principle, setting the restraint so that [50] In practice, while the bound state sampling in the HREM stage allows quite an accurate reconstruction of the PMF in the bottom of the well, zones at larger distances/higher energies towards unbound states are statistically noisy. This is so since solute torsional tempering with no water-solute rescaling [49] (as done in our HREM approach) does not accelerate relative host-guest diffusion, in a such a way that the expected shortest τ off for the weakest binder among all host-guest pairs (TEMOA-G5, K d 10 −3 M) should be of the order of the microseconds [35,36] in any GE state, making de facto unattainable the brute force sampling of unbound states in the HREM stage and hence the direct calculation of K d .…”