Water movement during ligand unbinding from receptor site.
Ontology highlight
ABSTRACT:
SUBMITTER: Chau PL
PROVIDER: S-EPMC1304335 | biostudies-literature | 2004 Jul
REPOSITORIES: biostudies-literature
Publications
Water movement during ligand unbinding from receptor site.
Biophysical journal 20040701 1
An 1-ns unbinding trajectory of retinol from the bovine serum retinol-binding protein has been obtained from molecular dynamics simulations. The behavior of water during ligand unbinding has never been studied in detail. I described a new method for defining a binding site, located the water molecules involved in the binding site, and examined their movements during unbinding. I found that there were only small changes in the binding site. During unbinding, the number of water molecules inside t ...[more]
Similar Datasets
Project description: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 extremely difficult task due to the long timescales involved. This gets further complicated by the presence of biophysical factors such as steric and solvation effects. In this work, we perform molecular dynamics (MD) simulations of the unbinding of a popular prototypical hydrophobic cavity-ligand system using a metadynamics-based approach that allows direct assessment of kinetic pathways and parameters. When constrained to move in an axial manner, the unbinding time is found to be on the order of 4,000 s. In accordance with previous studies, we find that the cavity must pass through a region of sharp wetting transition manifested by sudden and high fluctuations in solvent density. When we remove the steric constraints on ligand, the unbinding happens predominantly by an alternate pathway, where the unbinding becomes 20 times faster, and the sharp wetting transition instead becomes continuous. We validate the unbinding timescales from metadynamics through a Poisson analysis, and by comparison through detailed balance to binding timescale estimates from unbiased MD. This work demonstrates that enhanced sampling can be used to perform explicit solvent MD studies at timescales previously unattainable, to our knowledge, obtaining direct and reliable pictures of the underlying physiochemical factors including free energies and rate constants.
| S-EPMC4593114 | biostudies-literature
Project description: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 (MD) simulations, often in quantitative agreement with experiments. However, only a qualitative picture of the ligand binding/unbinding paths can be obtained through a conventional analysis of the MD trajectories. Besides, the higher degree of manual effort involved in analyzing pathways limits its applicability in large-scale drug discovery. Here, we address this limitation by introducing an automated approach for analyzing molecular transition paths with a particular focus on protein-ligand dissociation. Our method is based on the dynamic time-warping algorithm, originally designed for speech recognition. We accurately classified molecular trajectories using a very generic descriptor set of contacts or distances. Our approach outperforms manual classification by distinguishing between parallel dissociation channels, within the pathways identified by visual inspection. Most notably, we could compute exit-path-specific ligand-dissociation kinetics. The unbinding timescale along the fastest path agrees with the experimental residence time, providing a physical interpretation to our entirely data-driven protocol. In combination with appropriate enhanced sampling algorithms, this technique can be used for the initial exploration of ligand-dissociation pathways as well as for calculating path-specific thermodynamic and kinetic properties.
| S-EPMC10927508 | biostudies-literature
Project description:We report simulations of full ligand exit pathways for the trypsin-benzamidine system, generated using the sampling technique WExplore. WExplore is able to observe millisecond-scale unbinding events using many nanosecond-scale trajectories that are run without introducing biasing forces. The algorithm generates rare events by dividing the coordinate space into regions, on-the-fly, and balancing computational effort between regions through cloning and merging steps, as in the weighted ensemble method. The averaged exit flux yields a ligand exit rate of 180 μs, which is within an order of magnitude of the experimental value. We obtain broad sampling of ligand exit pathways, and visualize our findings using conformation space networks. The analysis shows three distinct exit channels, two of which are formed through large, rare motions of the loop regions in trypsin. This broad set of ligand-bound poses is then used to investigate general properties of ligand binding: we observe both a direct stabilizing effect of ligand-protein interactions and an indirect destabilizing effect on intraprotein interactions that is induced by the ligand. Significantly, the crystallographic binding poses are distinguished not only because their ligands induce large stabilizing effects, but also because they induce relatively low indirect destabilizations.
| S-EPMC5340210 | biostudies-literature
Project description:The translocator protein (TSPO), previously known as the peripheral benzodiazepine receptor, is of longstanding medical interest as both a biomarker for neuroinjury and a potential drug target for neuroinflammation and other disorders. Recently, it was shown that ligand residence time is a key factor determining steroidogenic efficacy of TSPO-binding compounds. This spurs interest in simulations of (un)binding pathways of TSPO ligands, which could reveal the molecular interactions governing ligand residence time. In this study, we use a weighted ensemble algorithm to determine the unbinding pathway for different poses of PK-11195, a TSPO ligand used in neuroimaging. In contrast with previous studies, our results show that PK-11195 does not dissociate directly into the solvent but instead dissociates via the lipid membrane by going between the transmembrane helices. We analyze this path ensemble in detail, constructing descriptors that can facilitate a general understanding of membrane-mediated ligand binding. We construct a set of Markov state models augmented with additional straightforward simulations to determine pose-specific ligand residence times. Together, we combine over 40 μs of trajectory data to form a coherent picture of the ligand binding landscape. We find that multiple starting poses yield residence times that roughly agree with the experimental quantity. The ligand binding transition states predicted by these Markov state models occur when PK-11195 is already in the membrane and involves only minimal ligand-protein interactions. This has implications for the design of new long-residence-time TSPO ligands.
| S-EPMC7820730 | biostudies-literature
Project description:Solvent reorganization is a major driving force of protein-ligand association, but the contribution of binding site waters to ligand affinity is poorly understood. We investigated how altered interactions with a water network can influence ligand binding to a receptor. A series of ligands of the A2A adenosine receptor, which either interacted with or displaced an ordered binding site water, were studied experimentally and by molecular dynamics simulations. An analog of the endogenous ligand that was unable to hydrogen bond to the ordered water lost affinity and this activity cliff was captured by molecular dynamics simulations. Two compounds designed to displace the ordered water from the binding site were then synthesized and evaluated experimentally, leading to the discovery of an A2A agonist with nanomolar activity. Calculation of the thermodynamic profiles resulting from introducing substituents that interacted with or displaced the ordered water showed that the gain of binding affinity was enthalpy driven. Detailed analysis of the energetics and binding site hydration networks revealed that the enthalpy change was governed by contributions that are commonly neglected in structure-based drug optimization. In particular, simulations suggested that displacement of water from a binding site to the bulk solvent can lead to large energy contributions. Our findings provide insights into the molecular driving forces of protein-ligand binding and strategies for rational drug design.
| S-EPMC8179138 | biostudies-literature
Project description:The nicotinic acetylcholine receptor is a prototype ligand-gated ion channel that mediates signal transduction in the neuromuscular junctions and other cholinergic synapses. The molecular basis for the energetics of ligand binding and unbinding is critical to our understanding of the pharmacology of this class of receptors. Here, we used steered molecular dynamics to investigate the unbinding of acetylcholine from the ligand-binding domain of human alpha7 nicotinic acetylcholine receptor along four different predetermined pathways. Pulling forces were found to correlate well with interactions between acetylcholine and residues in the binding site during the unbinding process. From multiple trajectories along these unbinding pathways, we calculated the potentials of mean force for acetylcholine unbinding. Four available methods based on Jarzynski's equality were used and compared for their efficiencies. The most probable pathway was identified to be along a direction approximately parallel to the membrane. The derived binding energy for acetylcholine was in good agreement with that derived from the experimental binding constant for acetylcholine binding protein, but significantly higher than that for the complete human alpha7 nicotinic acetylcholine receptor. In addition, it is likely that several intermediate states exist along the unbinding pathways.
| S-EPMC2546508 | biostudies-literature
Project description:The computational prediction of unbinding rate constants is presently an emerging topic in drug design. However, the importance of predicting kinetic rates is not restricted to pharmaceutical applications. Many biotechnologically relevant enzymes have their efficiency limited by the binding of the substrates or the release of products. While aiming at improving the ability of our model enzyme haloalkane dehalogenase DhaA to degrade the persistent anthropogenic pollutant 1,2,3-trichloropropane (TCP), the DhaA31 mutant was discovered. This variant had a 32-fold improvement of the catalytic rate toward TCP, but the catalysis became rate-limited by the release of the 2,3-dichloropropan-1-ol (DCP) product from its buried active site. Here we present a computational study to estimate the unbinding rates of the products from DhaA and DhaA31. The metadynamics and adaptive sampling methods were used to predict the relative order of kinetic rates in the different systems, while the absolute values depended significantly on the conditions used (method, force field, and water model). Free energy calculations provided the energetic landscape of the unbinding process. A detailed analysis of the structural and energetic bottlenecks allowed the identification of the residues playing a key role during the release of DCP from DhaA31 via the main access tunnel. Some of these hot-spots could also be identified by the fast CaverDock tool for predicting the transport of ligands through tunnels. Targeting those hot-spots by mutagenesis should improve the unbinding rates of the DCP product and the overall catalytic efficiency with TCP.
| S-EPMC6331733 | biostudies-literature
Project description: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 theoretical descriptions. Here, we devise a holistic, implicit-solvent, multimethod approach to predict the (un)binding kinetics for a generic ligand-pocket model. We use the variational implicit-solvent model (VISM) to calculate the solute-solvent interfacial structures and the corresponding free energies, and combine the VISM with the string method to obtain the minimum energy paths and transition states between the various metastable ("dry" and "wet") hydration states. The resulting dry-wet transition rates are then used in a spatially dependent multistate continuous-time Markov chain Brownian dynamics simulation and the related Fokker-Planck equation calculations of the ligand stochastic motion, providing the mean first-passage times for binding and unbinding. We find the hydration transitions to significantly slow down the binding process, in semiquantitative agreement with existing explicit-water simulations, but significantly accelerate the unbinding process. Moreover, our methods allow the characterization of nonequilibrium hydration states of pocket and ligand during the ligand movement, for which we find substantial memory and hysteresis effects for binding vs. unbinding. Our study thus provides a significant step forward toward efficient, physics-based interpretation and predictions of the complex kinetics in realistic ligand-receptor systems.
| S-EPMC6660732 | biostudies-literature
Project description:We use a recently proposed method called Spectral Gap Optimization of Order Parameters (SGOOP) [P. Tiwary and B. J. Berne, Proc. Natl. Acad. Sci. U. S. A. 113, 2839 (2016)], to determine an optimal 1-dimensional reaction coordinate (RC) for the unbinding of a bucky-ball from a pocket in explicit water. This RC is estimated as a linear combination of the multiple available order parameters that collectively can be used to distinguish the various stable states relevant for unbinding. We pay special attention to determining and quantifying the degree to which water molecules should be included in the RC. Using SGOOP with under-sampled biased simulations, we predict that water plays a distinct role in the reaction coordinate for unbinding in the case when the ligand is sterically constrained to move along an axis of symmetry. This prediction is validated through extensive calculations of the unbinding times through metadynamics and by comparison through detailed balance with unbiased molecular dynamics estimate of the binding time. However when the steric constraint is removed, we find that the role of water in the reaction coordinate diminishes. Here instead SGOOP identifies a good one-dimensional RC involving various motional degrees of freedom.
| S-EPMC4975749 | biostudies-other
Project description:Protein-ligand interactions taking place far away from the active site, during ligand binding or release, may determine molecular specificity and activity. However, obtaining information about these interactions with experimental or computational methods remains difficult. The computational tool presented in this article, MoMA-LigPath, is based on a mechanistic representation of the molecular system, considering partial flexibility, and on the application of a robotics-inspired algorithm to explore the conformational space. Such a purely geometric approach, together with the efficiency of the exploration algorithm, enables the simulation of ligand unbinding within short computing time. Ligand unbinding pathways generated by MoMA-LigPath are a first approximation that can provide useful information about protein-ligand interactions. When needed, this approximation can be subsequently refined and analyzed using state-of-the-art energy models and molecular modeling methods. MoMA-LigPath is available at http://moma.laas.fr. The web server is free and open to all users, with no login requirement.
| S-EPMC3692135 | biostudies-literature