SEEKR2: Versatile Multiscale Milestoning Utilizing the OpenMM 7.5 Molecular Dynamics Engine

Votapka, Lane; Stokely, Andrew; Ojha, Anupam; Amaro, Rommie E.

doi:10.33774/chemrxiv-2021-pplfs

Cited by 2 publications

(1 citation statement)

References 41 publications

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“…A recent study using the MMVT SEEKR approach has predicted the k off of the trypsin–benzamidine complex to be 990 ± 70 s –1 , a value that is relatively closer to the experimental number compared to the previous result of 62 ± 6 s –1 (Table ). However, the fact that a virtually identical simulation scheme can produce results that are more than 1 order of magnitude apart clearly shows the high level of uncertainty involved in the milestoning approach.…”

Section: Discussionsupporting

confidence: 60%

Markovian Weighted Ensemble Milestoning (M-WEM): Long-Time Kinetics from Short Trajectories

Ray

Stone

Andricioaei

2021

J. Chem. Theory Comput.

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We introduce a rare-event sampling scheme, named Markovian Weighted Ensemble Milestoning (M-WEM), which inlays a weighted ensemble framework within a Markovian milestoning theory to efficiently calculate thermodynamic and kinetic properties of long-time-scale biomolecular processes from short atomistic molecular dynamics simulations. M-WEM is tested on the Muller−Brown potential model, the conformational switching in alanine dipeptide, and the millisecond time-scale protein−ligand unbinding in a trypsin−benzamidine complex. Not only can M-WEM predict the kinetics of these processes with quantitative accuracy but it also allows for a scheme to reconstruct a multidimensional free-energy landscape along additional degrees of freedom, which are not part of the milestoning progress coordinate. For the ligand−receptor system, the experimental residence time, association and dissociation kinetics, and binding free energy could be reproduced using M-WEM within a simulation time of a few hundreds of nanoseconds, which is a fraction of the computational cost of other currently available methods, and close to 4 orders of magnitude less than the experimental residence time. Due to the high accuracy and low computational cost, the M-WEM approach can find potential applications in kinetics and free-energy-based computational drug design.

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Section: Discussionsupporting

confidence: 60%

Markovian Weighted Ensemble Milestoning (M-WEM): Long-Time Kinetics from Short Trajectories

Ray

Stone

Andricioaei

2021

J. Chem. Theory Comput.

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show abstract

Markovian Weighted Ensemble Milestoning (M-WEM): Long-time Kinetics from Short Trajectories

Andricioaei

2021

Preprint

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We introduce a rare-event sampling scheme, named Markovian Weighted Ensemble Milestoning (M-WEM), which inlays the weighted ensemble framework within a Markovian milestoning theory to efficiently calculate thermodynamic and kinetic properties of long-timescale biomolecular processes from short atomistic molecular dynamics simulations. We then showcase the application of this method to the Muller Brown potential model, the conformational switching in alanine dipeptide, and the millisecond timescale protein-ligand unbinding in the trypsin-benzamidine complex. Not only can we predict the kinetics of these processes with quantitative accuracy, but we also present a scheme to reconstruct a multidimensional free energy landscape, along additional degrees of freedom which are not part of the milestoning progress coordinate. For the ligand-receptor system, the experimental residence time, association and dissociation kinetics, and binding free energy could be reproduced using M-WEM approach within a few hundreds of nanoseconds simulation time, which is a fraction of the computational cost of other currently available methods, and close to four orders of magnitude less than the experimental residence time. Due to the high accuracy and low computational cost the M-WEM approach can find potential application in kinetics and free energy based computational drug design.

show abstract

SEEKR2: Versatile Multiscale Milestoning Utilizing the OpenMM 7.5 Molecular Dynamics Engine

Cited by 2 publications

References 41 publications

Markovian Weighted Ensemble Milestoning (M-WEM): Long-Time Kinetics from Short Trajectories

Markovian Weighted Ensemble Milestoning (M-WEM): Long-Time Kinetics from Short Trajectories

Markovian Weighted Ensemble Milestoning (M-WEM): Long-time Kinetics from Short Trajectories

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