Related papers: Exhaustive Search of Ligand Binding Pathways via V…
We here report on non-equilibrium targeted Molecular Dynamics simulations as tool for the estimation of protein-ligand unbinding kinetics. Correlating simulations with experimental data from SPR kinetics measurements and X-ray…
The dynamic nature of proteins, influenced by ligand interactions, is essential for comprehending protein function and progressing drug discovery. Traditional structure-based drug design (SBDD) approaches typically target binding sites with…
We present a new method that combines alchemical transformation with physical pathway to accurately and efficiently compute the absolute binding free energy of receptor-ligand complex. Currently, the double decoupling method (DDM) and the…
Accurate prediction of protein-ligand binding affinities is an essential challenge in structure-based drug design. Despite recent advances in data-driven methods for affinity prediction, their accuracy is still limited, partially because…
Rebinding kinetics of molecular ligands plays a critical role in biomachinery, from regulatory networks to protein transcription, and is also a key factor for designing drugs and high-precision biosensors.In this study, we investigate…
Protein-ligand binding is essential to almost all life processes. The understanding of protein-ligand interactions is fundamentally important to rational drug design and protein design. Based on large scale data sets, we show that protein…
Accurate protein structural ensembles can be determined with metainference, a Bayesian inference method that integrates experimental information with prior knowledge of the system and deals with all sources of uncertainty and errors as well…
Ligand diffusion through proteins is a fundamental process governing biological signaling and enzymatic catalysis. The complex topology of protein tunnels results in difficulties with computing ligand escape pathways by standard molecular…
To accelerate exploration of chemical space, it is necessary to identify the compounds that will provide the most additional information or value. A large-scale analysis of mononuclear octahedral transition metal complexes deposited in an…
We present a molecular simulation method to simultaneously find multiple transition pathways, and their associated free-energy profiles. The scheme extends path-metadynamics (PMD) [Phys. Rev. Lett. 109, 020601 (2012)] with multiple paths…
Ligand-receptor binding and unbinding are fundamental biomolecular processes and particularly essential to drug efficacy. Environmental water fluctuations, however, impact the corresponding thermodynamics and kinetics and thereby challenge…
Comprehensive knowledge of protein-ligand interactions should provide a useful basis for annotating protein functions, studying protein evolution, engineering enzymatic activity, and designing drugs. To investigate the diversity and…
Accurate prediction of protein-ligand binding affinities is crucial in drug discovery, particularly during hit-to-lead and lead optimization phases, however, limitations in ligand force fields continue to impact prediction accuracy. In this…
Enzyme-based systems have been shown to undergo directional motion in response to their substrate gradient. Here, we formulate a kinetic model to analyze the directional movement of an ensemble of protein molecules in response to a gradient…
Receptor-ligand interactions are essential for biological function and their binding strength is commonly explained in terms of static lock-and-key models based on molecular complementarity. However, detailed information of the full…
A key factor influencing a drug's efficacy is its residence time in the binding pocket of the host protein. Using atomistic computer simulation to predict this residence time and the associated dissociation process is a desirable but…
Fragment-based drug design is a promising strategy leveraging the binding of small chemical moieties that can efficiently guide drug discovery. The initial step of fragment identification remains challenging, as fragments often bind weakly…
According to implicit ligand theory, the standard binding free energy is an exponential average of the binding potential of mean force (BPMF), an exponential average of the interaction energy between the ligand apo ensemble and a rigid…
Empirical scoring functions based on either molecular force fields or cheminformatics descriptors are widely used, in conjunction with molecular docking, during the early stages of drug discovery to predict potency and binding affinity of a…
Coarse-graining of fully atomistic molecular dynamics simulations is a long-standing goal in order to allow the description of processes occurring on biologically relevant timescales. For example, the prediction of pathways, rates and…