Perspectives on Ligand/Protein Binding Kinetics Simulations: Force Fields, Machine Learning, Sampling, and User-Friendliness

Abstract

Computational techniques applied to drug discovery have gained considerable popularity for their ability to filter potentially active drugs from inactive ones, reducing the time scale and costs of preclinical investigations. The main focus of these studies has historically been the search for compounds endowed with high affinity for a specific molecular target to ensure the formation of stable and long-lasting complexes. Recent evidence has also correlated the in vivo drug efficacy with its binding kinetics, thus opening new fascinating scenarios for ligand/protein binding kinetic simulations in drug discovery. The present article examines the state of the art in the field, providing a brief summary of the most popular and advanced ligand/protein binding kinetics techniques and evaluating their current limitations and the potential solutions to reach more accurate kinetic models. Particular emphasis is put on the need for a paradigm change in the present methodologies toward ligand and protein parametrization, the force field problem, characterization of the transition states, the sampling issue, and algorithms' performance, user-friendliness, and data openness.

Mechanism of Ligand Binding to Theophylline RNA Aptamer

“…These simulations have been used to study biomolecular binding mechanisms despite the difficulty in capturing both ligand dissociation and binding processes. To simulate these processes and forecast binding kinetic rates, improved sampling techniques have been developed, including the Weighted Ensemble, mile-stoning method, GaMD, Metadynamics, Markov State Modeling, Random Acceleration MD, and scaled MD. , In LiGaMD simulations, the accelerations of ligand kinetic rates were precisely estimated using Kramers’ rate theory. The simulations have allowed us to map the rugged energy landscape of RNA, investigate the RNA-methylxanthine interaction in detail, and evaluate the binding thermodynamics and kinetics of TEP.…”

The Open Force Field Initiative: Open Software and Open Science for Molecular Modeling

“…The work of Conflitti, Raniolo and Limongelli 186 neatly summarizes the need for both openness and standardization in this area as follows: “...we believe existing and new FFs should be developed following the principles of data openness. Most FFs use diverse definitions for residue names, atom names, or types, which may confuse a novice user.…”

Computational screening of the effects of mutations on protein-protein off-rates and dissociation mechanisms by τRAMD

“…10 Consequently, enhanced sampling methods are being developed to address this limitation and some of these have been used to study protein-protein dissociation, e.g., metadynamics, scaled MD, Gaussian accelerated MD (GaMD), weighted ensemble (WE) MD, adaptive sampling to compute Markov state models (MSMs), and umbrella sampling (US). [10][11][12][13][14] One of the most well-studied protein-protein complexes is that of the ribonuclease barnase (Bn) bound to its inhibitor barstar (Bs). It is considered a challenging target as it is one of the tightest known protein-protein complexes, with a residence time of ~ 75h and Kd on the order of 10 -14 M in the wild type (WT) form 15 .…”

“…The S1-P1 and S2'-P2' interacting sites are highlighted. The primary binding loop (residues [11][12][13][14][15][16][17][18][19] and the secondary binding loop (34)(35)(36)(37)(38)(39) of BPTI are colored white and pink, respectively. The two insets show the interacting residues in the BT-BPTI and BCT-BPTI structures.…”

“…The copyright holder for this preprint this version posted March 14, 2024. ; https://doi.org/10.1101/2024.03.12.584688 doi: bioRxiv preprint ensemble (WE) MD, adaptive sampling to compute Markov state models (MSMs), and umbrella sampling (US). [10][11][12][13][14] One of the most well-studied protein-protein complexes is that of the ribonuclease barnase (Bn) bound to its inhibitor barstar (Bs). It is considered a challenging target as it is one of the tightest known protein-protein complexes, with a residence time of ~ 75h and Kd on the order of 10 -14 M in the wild type (WT) form 15 .…”