SEEKR2: Versatile Multiscale Milestoning Utilizing the OpenMM Molecular Dynamics Engine

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

doi:10.26434/chemrxiv-2021-pplfs-v2

Cited by 3 publications

(3 citation statements)

References 50 publications

(72 reference statements)

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“…k − = 1/⟨t⟩j. SEEKR is one such approach (Votapka et al, 2017(Votapka et al, , 2022 that has used this formalism to determine an association rate of 9 × 10 8 M −1 s −1 for Ca 2+ binding to TnC (Votapka and Amaro, 2015).…”

Section: Computational Approachesmentioning

confidence: 99%

Myofilament-associated proteins with intrinsic disorder (MAPIDs) and their resolution by computational modeling

Sun

Kekenes‐Huskey

2023

Quart. Rev. Biophys.

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The cardiac sarcomere is a cellular structure in the heart that enables muscle cells to contract. Dozens of proteins belong to the cardiac sarcomere, which work in tandem to generate force and adapt to demands on cardiac output. Intriguingly, the majority of these proteins have significant intrinsic disorder that contributes to their functions, yet the biophysics of these intrinsically disordered regions (IDRs) have been characterized in limited detail. In this review, we first enumerate these myofilament-associated proteins with intrinsic disorder (MAPIDs) and recent biophysical studies to characterize their IDRs. We secondly summarize the biophysics governing IDR properties and the state-of-the-art in computational tools toward MAPID identification and characterization of their conformation ensembles. We conclude with an overview of future computational approaches toward broadening the understanding of intrinsic disorder in the cardiac sarcomere.

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Section: Computational Approachesmentioning

confidence: 99%

Myofilament-associated proteins with intrinsic disorder (MAPIDs) and their resolution by computational modeling

Sun

Kekenes‐Huskey

2023

Quart. Rev. Biophys.

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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. [93][94][95] MD simulations are run using the OpenMM simulation engine, while BD simulations are run using the Browndye software. 96 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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“…While experimental measurements of binding/unbinding kinetics and thermodynamics are possible, accurate and efficient computational predictions remain attractive. SEEKR is a multiscale, simulation-based, enhanced sampling method used to characterize the kinetics and thermodynamics of a variety of binding/unbinding systems [9][10][11][12][13][14][15] .…”

Section: Introductionmentioning

confidence: 99%

Prediction of Threonine-Tyrosine Kinase Receptor-Ligand Unbinding Kinetics with Multiscale Milestoning and Metadynamics

Votapka,

Ojha,

Asada

et al. 2024

Preprint

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Accurately describing protein-ligand binding and unbinding kinetics remains challenging. Computational calculations are difficult and costly, while experimental measurements often lack molecular detail and can be unobtainable. Here we extend our multiscale milestoning method, Simulation-Enabled Estimation of Kinetics Rates (SEEKR), with metadynamics molecular dynamics simulations to yield accurate small molecule drug residence times. Using the pharmaceutically relevant threonine-tyrosine kinase (TTK) and eight long-residence-time (tens of seconds to hours) inhibitors, we demonstrate accurate prediction of absolute and rank-ordered ligand residence times and free energies of binding.TOC Graphic

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SEEKR2: Versatile Multiscale Milestoning Utilizing the OpenMM Molecular Dynamics Engine

Cited by 3 publications

References 50 publications

Myofilament-associated proteins with intrinsic disorder (MAPIDs) and their resolution by computational modeling

Myofilament-associated proteins with intrinsic disorder (MAPIDs) and their resolution by computational modeling

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

Prediction of Threonine-Tyrosine Kinase Receptor-Ligand Unbinding Kinetics with Multiscale Milestoning and Metadynamics

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