Nudged-elastic band used to find reaction coordinates based on the free energy

Bohner, Matthias U.; Zeman, Johannes; Smiatek, Jens; Arnold, Axel; Kästner, Johannes

doi:10.1063/1.4865220

Cited by 32 publications

(37 citation statements)

References 62 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Furthermore, we showed that by using an a posteriori statistical analysis (33) one can also establish the reliability of the kinetics thus generated. The use of metadynamics for obtaining kinetic information is still in its infancy, however its usefulness has been tested by us and other groups in a range of systems (15,(33)(34)(35)(36).…”

mentioning

confidence: 99%

Kinetics of protein–ligand unbinding: Predicting pathways, rates, and rate-limiting steps

Tiwary

Limongelli

Salvalaglio

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

355

428

View full text Add to dashboard Cite

The ability to predict the mechanisms and the associated rate constants of protein-ligand unbinding is of great practical importance in drug design. In this work we demonstrate how a recently introduced metadynamics-based approach allows exploration of the unbinding pathways, estimation of the rates, and determination of the rate-limiting steps in the paradigmatic case of the trypsin-benzamidine system. Protein, ligand, and solvent are described with full atomic resolution. Using metadynamics, multiple unbinding trajectories that start with the ligand in the crystallographic binding pose and end with the ligand in the fully solvated state are generated. The unbinding rate k off is computed from the mean residence time of the ligand. Using our previously computed binding affinity we also obtain the binding rate k on . Both rates are in agreement with reported experimental values. We uncover the complex pathways of unbinding trajectories and describe the critical ratelimiting steps with unprecedented detail. Our findings illuminate the role played by the coupling between subtle protein backbone fluctuations and the solvation by water molecules that enter the binding pocket and assist in the breaking of the shielded hydrogen bonds. We expect our approach to be useful in calculating rates for general protein-ligand systems and a valid support for drug design.protein-ligand unbinding | kinetics | enhanced sampling | drug design U nderstanding the thermodynamics and kinetics of proteinligand interactions is of paramount relevance in the early stages of drug discovery (1-3). So far the major emphasis has been placed on predicting the most likely binding pose as determined by the highest binding affinity (4, 5). In contrast, it has not been possible to predict the pathways for unbinding and the associated rates. However, it is by now well-recognized that one of the most pertinent factors for sustained drug efficacy and safety is not just its affinity, but possibly even more so, the mean lifetime of the protein-ligand complex (1-3). The latter property is strictly related to the time during which the ligand remains in the binding site (1, 2), and is typically expressed by its inverse, the dissociation rate k off (2). In principle k off should be amenable to calculations through all-atom molecular dynamics (MD) simulations. These simulations could give detailed and useful insights into the atomic interactions at work during unbinding, especially in the ephemeral but kinetically most relevant transition state ensemble (TSE) (6, 7). Such information is of great value in designing modifications of the ligand that might improve its pharmaceutical properties.However, despite the potential of MD simulations no such calculation has yet been reported. This is a consequence of the limited timescales of MD simulations. Even with the most modern purpose-built supercomputers or massive distributed computing, one can barely reach the timescale of milliseconds (3). Unfortunately most of the reported ligand-protein dissociation times fa...

show abstract

mentioning

confidence: 99%

Kinetics of protein–ligand unbinding: Predicting pathways, rates, and rate-limiting steps

Tiwary

Limongelli

Salvalaglio

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

355

428

View full text Add to dashboard Cite

show abstract

“…Therefore, a second group of methods founded on TPT implement the chain-of-states approach, which assumes that the transition path can be meaningfully encoded as a series or chain of structures (also referred to as images) [ 342 , 607 , 620 – 623 ]. These methods can track an arbitrary number of progress coordinates while restraining sampling to effectively one dimension.…”

Section: Categorization By Algorithmic Frameworkmentioning

confidence: 99%

“…Generally, NEB methods require that the energy landscape be relatively smooth and are not effective on rugged energy landscapes [ 619 ]. Remedies have been proposed by having NEB methods operate on the free energy landscape [ 623 ], which is expected to be smoother, or by introducing temperature corrections to the MEP [ 626 ]. Caution must be exercised not to double count entropy when operating on free energy landscapes.…”

Section: Categorization By Algorithmic Frameworkmentioning

confidence: 99%

Principles and Overview of Sampling Methods for Modeling Macromolecular Structure and Dynamics

et al. 2016

View full text Add to dashboard Cite

Investigation of macromolecular structure and dynamics is fundamental to understanding how macromolecules carry out their functions in the cell. Significant advances have been made toward this end in silico, with a growing number of computational methods proposed yearly to study and simulate various aspects of macromolecular structure and dynamics. This review aims to provide an overview of recent advances, focusing primarily on methods proposed for exploring the structure space of macromolecules in isolation and in assemblies for the purpose of characterizing equilibrium structure and dynamics. In addition to surveying recent applications that showcase current capabilities of computational methods, this review highlights state-of-the-art algorithmic techniques proposed to overcome challenges posed in silico by the disparate spatial and time scales accessed by dynamic macromolecules. This review is not meant to be exhaustive, as such an endeavor is impossible, but rather aims to balance breadth and depth of strategies for modeling macromolecular structure and dynamics for a broad audience of novices and experts.

show abstract

“…This methodology requires the identification of minimum energy paths (MEPs) that are traversed between pristine and defected states of the material, including the saddle point that characterizes the lowest energy barrier between these states. Techniques such as the nudged-elastic band (NEB) method can be used for such purposes, as was done by Zhu and Li 43 and by Bohner et al 44 Nguyen et al have also used the example of dislocation nucleation at crystal surfaces to study the strengths and limitations of several TST approaches, 45 including both harmonic (hTST) and quasiharmonic approximations of TST as well as a variational-based formulation (VTST). Their results provide physical insight on both the nucleation process at room temperature, and its rate sensitivity.…”

mentioning

confidence: 99%

Review Article: Case studies in future trends of computational and experimental nanomechanics

Tadmor

Kysar

Zimmerman

et al. 2017

Journal of Vacuum Science &Amp; Technology A: Vacuum, Surfaces, and Films

View full text Add to dashboard Cite

With rapidly increasing numbers of studies of new and exotic material uses for perovskites and quasicrystals, these demand newer instrumentation and simulation developments to resolve the revealed complexities. One such set of observational mechanics at the nanoscale is presented here for somewhat simpler material systems. The expectation is that these approaches will assist those materials scientists and physicists needing to verify atomistic potentials appropriate to the nanomechanical understanding of increasingly complex solids. The five following segments from nine University, National and Industrial Laboratories both review and forecast where some of the important approaches will allow a confirming of how in situ mechanics and nanometric visualization might unravel complex phenomena. These address two-dimensional structures, temporal models for the nanoscale, atomistic and multiscale friction fundamentals, nanoparticle surfaces and interfaces a) Electronic

show abstract

Nudged-elastic band used to find reaction coordinates based on the free energy

Cited by 32 publications

References 62 publications

Kinetics of protein–ligand unbinding: Predicting pathways, rates, and rate-limiting steps

Kinetics of protein–ligand unbinding: Predicting pathways, rates, and rate-limiting steps

Principles and Overview of Sampling Methods for Modeling Macromolecular Structure and Dynamics

Review Article: Case studies in future trends of computational and experimental nanomechanics

Contact Info

Product

Resources

About