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The dissociation of ligands from proteins and other biomacromolecules occurs over a wide range of timescales. For most pharmaceutically relevant inhibitors, these timescales are far beyond those that are accessible by conventional molecular…
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…
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…
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…
Large parallel gains in the development of both computational resources as well as sampling methods have now made it possible to simulate dissociation events in ligand-protein complexes with all--atom resolution. Such encouraging progress,…
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…
Here we present a novel method for the analysis of transport processes in proteins and its implementation called CaverDock. Our method is based on a modified molecular docking algorithm. It iteratively places the ligand along the access…
Protein folding is the intricate process by which a linear sequence of amino acids self-assembles into a unique three-dimensional structure. Protein folding kinetics is the study of pathways and time-dependent mechanisms a protein undergoes…
In drug discovery, molecular dynamics (MD) simulation for protein-ligand binding provides a powerful tool for predicting binding affinities, estimating transport properties, and exploring pocket sites. There has been a long history of…
The increasing number of protein-based metamaterials demands reliable and efficient theoretical and computational methods to study the physicochemical properties they may display. In this regard, we develop a simulation strategy based on…
The prediction of the three-dimensional structures of the native state of proteins from the sequences of their amino acids is one of the most important challenges in molecular biology. An essential ingredient to solve this problem within…
The limits of molecular dynamics (MD) simulations of macromolecules are steadily pushed forward by the relentless developments of computer architectures and algorithms. This explosion in the number and extent (in size and time) of MD…
The stochastic motions of a diffusing particle contain information concerning the particle's interactions with binding partners and with its local environment. However, accurate determination of the underlying diffusive properties, beyond…
Unraveling the dynamical motions of biomolecules is essential for bridging their structure and function, yet it remains a major computational challenge. Molecular dynamics (MD) simulation provides a detailed depiction of biomolecular…
The response of proteins to chemical reactions or impulsive excitation that occurs within the molecule has fascinated chemists for decades. In recent years ultrafast X-ray studies have provided ever more detailed information about the…
We have previously shown that Good-Turing statistics can be applied to molecular dynamics trajectories to estimate the probability of observing completely new (thus far unobserved) biomolecular structures, and showed that the method is…
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…
Simulating stochastic differential equations (SDEs) in bounded domains, presents significant computational challenges due to particle exit phenomena, which requires accurate modeling of interior stochastic dynamics and boundary…
A novel approach to simulate simple protein-ligand systems at large time- and length-scales is to couple Markov state models (MSMs) of molecular kinetics with particle-based reaction-diffusion (RD) simulations, MSM/RD. Currently, MSM/RD…