Accelerating the Calculation of Protein-Ligand Binding Free Energy and Residence Times using Dynamically Optimized Collective Variables

Abstract

Elucidation of the ligand/protein binding interaction is of paramount relevance in pharmacology to increase the success rate of drug design. To this end a number of computational methods have been proposed, however all of them suffer from limitations since the ligand binding/unbinding transitions to the molecular target involve many slow degrees of freedom that hamper a full characterization of the binding process.Being able to express this transition in simple and general slow degrees of freedom, would give a distinctive advantage, since it would require minimal knowledge of the system under study, while in turn it would elucidate its physics and accelerate the convergence speed of enhanced sampling methods relying on collective variables. In this study we pursuit this goal by combining for the first time Variation Approach to Conformational dynamics with Funnel-Metadynamics. In so doing, we predict for the benzamidine/trypsin system the ligand binding mode, and we accurately compute the absolute protein-ligand binding free energy and unbinding rate at unprecedented low computational cost. Finally, our simulation protocol reveals the energetics and structural details of the ligand binding mechanism and shows that water and binding pocket solvation/desolvation are the dominant slow degrees of freedom.

Combining Monte Carlo and Molecular Dynamics Simulations for Enhanced Binding Free Energy Estimation through Markov State Models

“…While these values will most likely be system dependent, the PMF projection seems to be a good indication for trusting the results, as shown in our previous study as well. 23 Similar to the funnel metadynamics approach, 48,49 our results indicate that a smart restriction of the search space largely facilitates convergence. Figure S4A shows the evolution of the Spearman and R 2 indicators when using the original spherical restriction for the same 40 initial trajectories (and up to 300 ns).…”

“…Besides, in these simulations, we have modified the simulation box, previously of spherical shape into a cylinder (see Figure S2 for a depiction of the new simulation box). This setup is similar in nature to the funnel metadynamics approach, 48,49 and the setup for fully flexible docking method introduced by Bertazzo et al 50 allowing complete exploration of the binding/unbinding process but restricting the (impossible) exploration of all solvated states and reducing the access to additional metastable surface states. The objective of this additional run is two-fold: i) check whether the longer time scales are sufficient to observe more transitions, and ii) avoid excessive sampling of secondary minima off-site, such as the ones mentioned in the previous section, which should improve the convergence of the estimation, particularly for the larger ligands.…”

An Enhanced Sampling Approach to the Induced Fit Docking Problem in Protein-Ligand Binding: the case of mono-ADP-ribosylation hydrolases inhibitors

“…However, the application of restraining potential caused a loss of the translational degrees of freedom of ligand in the solvated state, which would need to be corrected when calculating the absolute free energy (ΔG_standard) [2, 37, 38, 68]. …”

“…It identifies new ligands by mapping biological activity data to distinct structural and energetic features of ligand-target complexes. In silico predictions of the poses and affinities of ligands for their biological targets constitute a key step of the approach [1, 2].…”

Ligand binding free energy and kinetics calculation in 2020

“…The method has proven to be successful in reproducing binding processes in ligand/protein and ligand/ DNA systems, predicting crystallographic binding modes and experimental binding free energies. 67,[161][162][163][164][165] FM allows overcoming many limitations of the previously described methods. In particular, while all the other methods provide a static representation of the ligand binding lacking any information about its mechanism of binding, in FM the ligand explores the whole binding path, from its fully solvated state to the final binding mode.…”