SEEKR2: Versatile Multiscale Milestoning Utilizing the OpenMM Molecular Dynamics Engine

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

doi:10.1021/acs.jcim.2c00501

Cited by 25 publications

(44 citation statements)

References 73 publications

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“…Here we describe a strategy that makes it possible to calculate accurately both quantities. We demonstrate this assertion with a state-of-the-art simulation of the Trypsin-Benzamidine system 2 – 13 and we find that the unbinding process can be more complex than what one could have anticipated. Although Trypsin-Benzamidine is one of the simplest cases of protein-ligand systems, high-resolution crystallographic experiments have recently demonstrated the presence of an extensive water structure in the binding cavity 14 .…”

Section: Introductionmentioning

confidence: 69%

Water regulates the residence time of Benzamidine in Trypsin

2022

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The process of ligand-protein unbinding is crucial in biophysics. Water is an essential part of any biological system and yet, many aspects of its role remain elusive. Here, we simulate with state-of-the-art enhanced sampling techniques the binding of Benzamidine to Trypsin which is a much studied and paradigmatic ligand-protein system. We use machine learning methods to determine efficient collective coordinates for the complex non-local network of water. These coordinates are used to perform On-the-fly Probability Enhanced Sampling simulations, which we adapt to calculate also the ligand residence time. Our results, both static and dynamic, are in good agreement with experiments. We find that the presence of a water molecule located at the bottom of the binding pocket allows via a network of hydrogen bonds the ligand to be released into the solution. On a finer scale, even when unbinding is allowed, another water molecule further modulates the exit time.

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Section: Introductionmentioning

confidence: 69%

Water regulates the residence time of Benzamidine in Trypsin

2022

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“…The recently developed version of SEEKR with Markovian milestoning with the Voronoi tessellations approach has been shown to estimate accurate binding kinetic rates with the simulation time reduced by a factor of ∼10 in comparison to the original SEEKR. 25 Using the trypsin-benzamidine model system as an example, the SEEKR 89 and its latest version SEEKR2 86 predicted the binding kinetic rates of (k on , k off ) at (12 ± 0.5 × 10 7 M −1 s −1 , 174 ± 9 s −1 ) and (2.4 ± 0.2 × 10 7 M −1 s −1 , 990 ± 130 s −1 ), respectively, being highly consistent with the corresponding experimental data of (2.9 × 10 7 M −1 s −1 , 600 s −1 ). Particularly, SEEKR2 27 was recently applied to predict the dissociation rates of a number of inhibitors for the Janus Kinase (JAK) system.…”

Section: Molecular Dynamics and Enhanced Sampling Methods For Predict...mentioning

confidence: 99%

Predicting Biomolecular Binding Kinetics: A Review

Wang

Hung

Koirala

et al. 2023

J. Chem. Theory Comput.

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Biomolecular binding kinetics including the association (k on ) and dissociation (k of f ) rates are critical parameters for therapeutic design of smallmolecule drugs, peptides, and antibodies. Notably, the drug molecule residence time or dissociation rate has been shown to correlate with their efficacies better than binding affinities. A wide range of modeling approaches including quantitative structure-kinetic relationship models, Molecular Dynamics simulations, enhanced sampling, and Machine Learning has been developed to explore biomolecular binding and dissociation mechanisms and predict binding kinetic rates. Here, we review recent advances in computational modeling of biomolecular binding kinetics, with an outlook for future improvements.

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“…SEEKR2 is an open-source software that automates the process of preparation, initiation, running, and analysis of milestoning calculations utilizing MD and Brownian dynamics (BD) simulations to estimate the kinetics and thermodynamics of receptor-ligand binding and unbinding. [29][30][31] MD simulations are run using the OpenMM simulation engine, while BD simulations are run using the Browndye software. 32 In the SEEKR2 multiscale milestoning approach, the phase space of the receptor-ligand complex is split into two regions, i.e., the MD and the BD region.…”

Section: Markovian Milestoning With Voronoi Tessellationsmentioning

confidence: 99%

Selectivity and ranking of tight-binding JAK-STAT inhibitors using Markovian milestoning with Voronoi tessellations

Ojha

Srivastava

Votapka

et al. 2022

Preprint

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Janus kinases (JAK) are a group of proteins in the non-receptor tyrosine kinase (NRTKs) family that play a crucial role in growth, survival, and angiogenesis. They are activated by cytokines through the Janus kinase - signal transducer and activator of transcription (JAK-STAT) signaling pathway. JAK-STAT signaling pathways have significant roles in the regulation of cell division, apoptosis, and immunity. Identification of the V617F mutation in the Janus homology 2 (JH2) domain of JAK2 leading to myeloproliferative disorders has stimulated great interest in the drug discovery community to develop JAK2-specific inhibitors. However, such inhibitors should be selective towards JAK2 over other JAKs and display an extended residence time. Recently, novel JAK2/STAT5 axis inhibitors (N-(1H-pyrazol-3-yl)pyrimidin-2-amino derivatives) have displayed extended residence times (hours or longer) on target and adequate selectivity excluding JAK3. To facilitate a deeper understanding of the kinase-inhibitor interactions and advance the development of such inhibitors, we utilize a multiscale Markovian milestoning with Voronoi tessellations (MMVT) approach within the Simulation-Enabled Estimation of Kinetic Rates v.2 (SEEKR2) program to rank-order these inhibitors based on their kinetic properties and further explain the selectivity of JAK2 inhibitors over JAK3. Our approach investigates the kinetic and thermodynamic properties of JAK-inhibitor complexes in a user-friendly, fast, efficient, and accurate manner compared to other brute force and hybrid enhanced sampling approaches.

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SEEKR2: Versatile Multiscale Milestoning Utilizing the OpenMM Molecular Dynamics Engine

Cited by 25 publications

References 73 publications

Water regulates the residence time of Benzamidine in Trypsin

Water regulates the residence time of Benzamidine in Trypsin

Predicting Biomolecular Binding Kinetics: A Review

Selectivity and ranking of tight-binding JAK-STAT inhibitors using Markovian milestoning with Voronoi tessellations

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