Related papers: Exhaustive Search of Ligand Binding Pathways via V…
Searching for reaction pathways describing rare events in large systems presents a long-standing challenge in chemistry and physics. Incorrectly computed reaction pathways result in the degeneracy of microscopic configurations and inability…
Due to the contribution of drug-target binding kinetics to drug efficacy, there is a high level of interest in developing methods to predict drug-target binding kinetic parameters. During the review period, a wide range of enhanced sampling…
Prediction of protein-ligand binding affinity is a major goal in drug discovery. Generally, free energy gap is calculated between two states (e.g., ligand binding and unbinding). The energy gap implicitly includes the effects of changes in…
Studying the pathways of ligand-receptor binding is essential to understand the mechanism of target recognition by small molecules. The binding free energy and kinetics of protein-ligand complexes can be computed using molecular dynamics…
We present two methods to reveal protein-ligand unbinding mechanisms in biased unbinding simulations by clustering trajectories into ensembles representing unbinding paths. The first approach is based on a contact principal component…
Protein-ligand interactions are crucial for a wide range of physiological processes. Many cellular functions result in these non-covalent `bonds' being mechanically strained, and this can be integral to proper cellular function. Broadly,…
The protein-ligand residence time, tau, influences molecular function in biological networks and has been recognized as an important determinant of drug efficacy. To predict tau, computational methods must overcome the problem that tau…
Disentangling the mechanistic details of a chemical reaction pathway is a hard problem that often requires a considerable amount of chemical intuition and a component of luck. Experiments struggle in observing short-life metastable…
The kinetics and dynamics of drug-protein binding and dissociation are crucial to understanding drug absorption and metabolism. Despite advances in artificial intelligence (AI) tools for drug-protein interaction studies, existing training…
We present a method to sample reactive pathways via biased molecular dynamics simulations in trajectory space. We show that the use of enhanced sampling techniques enables unconstrained exploration of multiple reaction routes. Time…
The molecular simulations solve the equation of motion of molecular systems, making 3D shapes of molecules four-dimensional by adding the time coordinate. These methods have a great potential in drug discovery because they can realistically…
Recent developments in enhanced sampling methods showed that it is possible to reconstruct ligand unbinding pathways with spatial and temporal resolution inaccessible to experiments. Ideally, such techniques should provide an atomistic…
Binding kinetic parameters can be correlated with drug efficacy, which led to the development of various computational methods for predicting binding kinetic rates and gaining insight into protein-drug binding paths and mechanisms in recent…
Metadynamics is a commonly used and successful enhanced sampling method. By the introduction of a history dependent bias which depends on a restricted number of collective variables(CVs) it can explore complex free energy surfaces…
Understanding the dynamics of biomolecular complexes, e.g., of protein-ligand (un)binding, requires the understanding of paths such systems take between metastable states. In MD simulation data, paths are usually not observable per se, but…
Computational drug discovery strategies can be broadly placed in two categories: ligand-based methods which identify novel molecules by similarity with known ligands, and structure-based methods which predict molecules with high-affinity to…
Protein-ligand (un)binding simulations are a recent focus of biased molecular dynamics simulations. Such binding and unbinding can occur via different pathways in and out of a binding site. We here present a theoretical framework how to…
We utilize a multiscale modeling framework to study the effect of shape, size and ligand composition on the efficacy of binding of a ligand-coated-particle to a substrate functionalized with the target receptors. First, we show how…
Azido-modified alanine residues (AlaN$_3$) are environment-sensitive, minimally invasive infrared probes for the site-specific investigation of protein structure and dynamics. Here, the capability of the label is investigated to query…
The accurate screening of candidate drug ligands against target proteins through computational approaches is of prime interest to drug development efforts. Such virtual screening depends in part on methods to predict the binding affinity…