Advances in Binding Free Energies Calculations: QM/MM-Based Free Energy Perturbation Method for Drug Design

Abstract

Multiple approaches have been devised and evaluated to computationally estimate binding free energies. Results using a recently developed Quantum Mechanics (QM)/Molecular Mechanics (MM) based Free Energy Perturbation (FEP) method suggest that this method has the potential to provide the most accurate estimation of binding affinities to date. The method treats ligands/inhibitors using QM while using MM for the rest of the system. The method has been applied and validated for a structurally diverse set of fructose 1,6- bisphosphatase (FBPase) inhibitors suggesting that the approach has the potential to be used as an integral part of drug discovery for both lead identification lead optimization, where there is a structure available. In addition, this QM/MM-based FEP method was shown to accurately replicate the anomalous hydration behavior exhibited by simple amines and amides suggesting that the method may also prove useful in predicting physical properties of molecules. While the method is about 5-fold more computationally demanding than conventional FEP, it has the potential to be less demanding on the end user since it avoids development of MM force field parameters for novel ligands and thereby eliminates this time-consuming step that often contributes significantly to the inaccuracy of binding affinity predictions using conventional FEP methods. The QM/MM-based FEP method has been extensively tested with respect to important considerations such as the length of the simulation required to obtain satisfactory convergence in the calculated relative solvation and binding free energies for both small and large structural changes between ligands. Future automation of the method and parallelization of the code is expected to enhance the speed and increase its use for drug design and lead optimization.

Towards chemical accuracy for alchemical free energy calculations with hybrid physics-based machine learning / molecular mechanics potentials

“…Another approach attempts to avoid the parameterization issue altogether by modeling the ligand using QM levels of theory, while treating the remaining atomic environment with an MM force field in a hybrid QM/MM potential [34][35][36][37][38]. QM/MM calculations are orders of magnitude more expensive than the equivalent calculation at the MM level, which has led to attempts to speed up these calculations by either using a low level of QM theory, or reducing the number of QM-level evaluations that are performed.…”

In silico Epitope Mapping of Glucose-6-Phosphate Isomerase: A Rheumatoid Arthritis Autoantigen

“…Predictions were verified with mass spectrometry-based epitope extraction [51,62,63] using synthetic peptides. The computational tools used for our predictions include the online Rosetta antibody server [39,56] for antibody modeling, and the ClusPro 2.0 server [57] for docking analyses.…”

Alchemical Hydration Free Energy Calculations Using Molecular Dynamics with Explicit Polarization and Induced Polarity Decoupling: An On-the-Fly Approach

“…A more computationally expensive method has also been used by Reddy et al for relative free energy calculations that encapsulates the dynamics of the simulation, termed QM/MM-FEP (quantum-mechanical-based free energy perturbation [53][54][55] ). At every MD step the energy and its gradients in the QM zone are calculated using semi-empirical AM1, while the QM/MM and MM interactions are calculated using the MM FF.…”