Related papers: Finding Multiple Reaction Pathways of Ligand Unbin…
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…
Determining the complete set of ligands' binding/unbinding pathways is important for drug discovery and to rationally interpret mutation data. Here we have developed a metadynamics-based technique that addressed this issue and allows…
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…
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…
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…
Understanding mechanisms of rare but important events in complex molecular systems, such as protein folding or ligand (un)binding, requires accurately mapping transition paths from an initial to a final state. The committor is the ideal…
This paper is devoted to the development of a theoretical and computational framework to efficiently sample the statistically significant thermally activated reaction pathways, in multi-dimensional systems obeying Langevin dynamics. We show…
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…
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…
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…
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…
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…
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…
Designing reaction pathways that maximize the production of a target compound in a given metabolic network is a fundamental problem in systems biology. In this study, we systematically explore the non-oxidative glycolysis metabolic network,…
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 discovery of transition pathways to unravel distinct reaction mechanisms and, in general, rare events that occur in molecular systems is still a challenge. Recent advances have focused on analyzing the transition path ensemble using the…
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…
The formation and dissociation of specific noncovalent interactions between a variety of macromolecules play a crucial role in the function of biological systems. During the last few years, three main lines of research led to a dramatic…
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…
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…