Abstract
In this study we have tested the performance of standard molecular dynamics simulations (MD), replicates of shorter standard MD simulations, and Hamiltonian Replica Exchange (HREM) simulations for the sampling of two macrocyclic hosts for guests delivery, characterized by induced fit (phenyl-based host) and conformation selection (naphtyl-based host), and of the ODR-BRD4(I) drug-receptor system where the ODR ligand can assume two main poses. For the optimization of the HREM simulation, we have proposed an on-the-fly iterative scheme for equalizing the acceptance ratio along the replica progression at constant replica number. We have found that while short MD replicates are able to sample as effectively as HREM the diverse conformational states in the phenyl-based host and in the ODR-BRD4(I) complex, in the naphtyl-based macrocycle, characterized by long-lived meta-stable states, HREM is the only viable alternative for a reliable canonical sampling of the rugged conformational landscape. Implications of these results for free energy calculation of binding free energy in drug-receptor systems are highlighted.
Supplementary weblinks
Title
Essential data and s/w for the paper "Dealing with induced fit, conformational selection and secondary poses in molecular dynamics simulations for reliable free energy predictions"
Description
inputs directory:
Contains the ORAC input files for all simulations reported in the paper
lib directory:
tpg and prm file for the potential models of 1 2 and the ODR-BRD4(I) systems
pdb directory: starting (crystallographic) PDB structures of 1, 2 and
of the ODR-BRD4(I) complex
tar directory:
Contains the tgz beta-version of the ORAC program with adaptive HREM. The distribution includes the source code, ancillary s/w and documentation
traj directory:
Contains the PDB trajectory files for all the simulations reported in the paper.
for the ODR-BRD4(I) complex water solvent is not included.
Actions
View