Dataset Information

Alchemical Binding Free Energy Calculations in AMBER20: Advances and Best Practices for Drug Discovery.

ABSTRACT: Predicting protein-ligand binding affinities and the associated thermodynamics of biomolecular recognition is a primary objective of structure-based drug design. Alchemical free energy simulations offer a highly accurate and computationally efficient route to achieving this goal. While the AMBER molecular dynamics package has successfully been used for alchemical free energy simulations in academic research groups for decades, widespread impact in industrial drug discovery settings has been minimal because of the previous limitations within the AMBER alchemical code, coupled with challenges in system setup and postprocessing workflows. Through a close academia-industry collaboration we have addressed many of the previous limitations with an aim to improve accuracy, efficiency, and robustness of alchemical binding free energy simulations in industrial drug discovery applications. Here, we highlight some of the recent advances in AMBER20 with a focus on alchemical binding free energy (BFE) calculations, which are less computationally intensive than alternative binding free energy methods where full binding/unbinding paths are explored. In addition to scientific and technical advances in AMBER20, we also describe the essential practical aspects associated with running relative alchemical BFE calculations, along with recommendations for best practices, highlighting the importance not only of the alchemical simulation code but also the auxiliary functionalities and expertise required to obtain accurate and reliable results. This work is intended to provide a contemporary overview of the scientific, technical, and practical issues associated with running relative BFE simulations in AMBER20, with a focus on real-world drug discovery applications.

SUBMITTER: Lee TS

PROVIDER: S-EPMC7686026 | biostudies-literature |

REPOSITORIES: biostudies-literature

ACCESS DATA

Similar Datasets

Project description:Recent advances in improved force fields and sampling methods have made it possible for the accurate calculation of protein–ligand binding free energies. Alchemical free energy perturbation (FEP) using an explicit solvent model is one of the most rigorous methods to calculate relative binding free energies. However, for cases where there are high energy barriers separating the relevant conformations that are important for ligand binding, the calculated free energy may depend on the initial conformation used in the simulation due to the lack of complete sampling of all the important regions in phase space. This is particularly true for ligands with multiple possible binding modes separated by high energy barriers, making it difficult to sample all relevant binding modes even with modern enhanced sampling methods. In this paper, we apply a previously developed method that provides a corrected binding free energy for ligands with multiple binding modes by combining the free energy results from multiple alchemical FEP calculations starting from all enumerated poses, and the results are compared with Glide docking and MM-GBSA calculations. From these calculations, the dominant ligand binding mode can also be predicted. We apply this method to a series of ligands that bind to c-Jun N-terminal kinase-1 (JNK1) and obtain improved free energy results. The dominant ligand binding modes predicted by this method agree with the available crystallography, while both Glide docking and MM-GBSA calculations incorrectly predict the binding modes for some ligands. The method also helps separate the force field error from the ligand sampling error, such that deviations in the predicted binding free energy from the experimental values likely indicate possible inaccuracies in the force field. An error in the force field for a subset of the ligands studied was identified using this method, and improved free energy results were obtained by correcting the partial charges assigned to the ligands. This improved the root-mean-square error (RMSE) for the predicted binding free energy from 1.9 kcal/mol with the original partial charges to 1.3 kcal/mol with the corrected partial charges.

Project description:Progress in the development of GPU-accelerated free energy simulation software has enabled practical applications on complex biological systems and fueled efforts to develop more accurate and robust predictive methods. In particular, this work re-examines concerted (a.k.a., one-step or unified) alchemical transformations commonly used in the prediction of hydration and relative binding free energies (RBFEs). We first classify several known challenges in these calculations into three categories: endpoint catastrophes, particle collapse, and large gradient-jumps. While endpoint catastrophes have long been addressed using softcore potentials, the remaining two problems occur much more sporadically and can result in either numerical instability (i.e., complete failure of a simulation) or inconsistent estimation (i.e., stochastic convergence to an incorrect result). The particle collapse problem stems from an imbalance in short-range electrostatic and repulsive interactions and can, in principle, be solved by appropriately balancing the respective softcore parameters. However, the large gradient-jump problem itself arises from the sensitivity of the free energy to large values of the softcore parameters, as might be used in trying to solve the particle collapse issue. Often, no satisfactory compromise exists with the existing softcore potential form. As a framework for solving these problems, we developed a new family of smoothstep softcore (SSC) potentials motivated by an analysis of the derivatives along the alchemical path. The smoothstep polynomials generalize the monomial functions that are used in most implementations and provide an additional path-dependent smoothing parameter. The effectiveness of this approach is demonstrated on simple yet pathological cases that illustrate the three problems outlined. With appropriate parameter selection, we find that a second-order SSC(2) potential does at least as well as the conventional approach and provides vast improvement in terms of consistency across all cases. Last, we compare the concerted SSC(2) approach against the gold-standard stepwise (a.k.a., decoupled or multistep) scheme over a large set of RBFE calculations as might be encountered in drug discovery.

Dataset Information

Alchemical Binding Free Energy Calculations in AMBER20: Advances and Best Practices for Drug Discovery.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets