Predicting Ligand Binding Kinetics Using a Markovian Milestoning with Voronoi Tessellations Multiscale Approach

Jagger, Benjamin R.; Ojha, Anupam; Amaro, Rommie E.

doi:10.26434/chemrxiv.12275165.v1

Cited by 11 publications

(39 citation statements)

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“…Concentric spherical milestones were placed at the following values of the RC: 1.0, 1.5, 2.0, 2.5, 3.0, 3.5, 4.0, 5.0, 6.0, 8.0, 10.0, 12.0, and 13.0 Å. These values are similar to previous studies 40,61 except for a few additional milestones as we were unable to observe energetically uphill transitions otherwise. The separation between milestones should be such that the transition timescales between one milestone to the other should be larger than the decay time of the velocity auto-correlation function of the RC.…”

Section: Methodssupporting

confidence: 74%

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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.

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Section: Methodssupporting

confidence: 74%

“…61 Despite cutting down the computational cost in sampling at the milestone interface, this approach still suffers from the Markovian assumption and can be significantly expensive for complex systems. 61…”

Section: Introductionmentioning

confidence: 99%

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

Andricioaei

2021

Preprint

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“…However, even with highly specialized hardware, brute-force MD has been limited to at best a fraction of a millisecond. 25,26 On the other hand, numerous enhanced sampling algorithms [27][28][29][30][31][32][33][34][35][36][37] have been employed for k of f calculations with more reasonable computational costs and the ability to achieve pharmacologically relevant timescales of sec-onds, minutes, and slower. Here we use one such enhanced sampling method "infrequent metadynamics" that has been employed to obtain unbiased estimates of dissociation kinetics in numerous systems.…”

Section: Introductionmentioning

confidence: 99%

Protein flexibility and dissociation pathway differentiation can explain onset of resistance mutations in kinases

Shekhar

Smith

Seeliger

et al. 2021

Preprint

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Understanding how point mutations can render a ligand or a drug ineffective against a given biological target is a problem of immense fundamental and practical relevance. Often the efficacy of such resistance mutations can be explained purely on a thermodynamic basis wherein the mutated system displays a reduced binding affinity for the ligand. However, the more perplexing and harder to explain situation is when two protein sequences have the same binding affinity for a drug. In this work, we demonstrate how all-atom molecular dynamics simulations, specifically using recent developments grounded in statistical mechanics and information theory, can provide a detailed mechanistic rationale for such variances. We establish the dissociation mechanism for the popular anti-cancer drug Imatinib (Gleevec) against wild-type and N387S mutant of Abl kinase. We show how this single point mutation triggers a non-local response in the protein's flexibility and eventually leads to pathway differentiation during dissociation. This pathway differentiation explains why Gleevec has a long residence time in the wild-type Abl, but for the mutant, by opening up a backdoor pathway for ligand exit, an order of magnitude shorter residence time is obtained. We thus believe that this work marks an efficient and scalable approach to pinpoint the molecular determinants of resistance mutations in biomolecular receptors of pharmacological relevance that are hard to explain using a simple structural perspective and require mechanistic and kinetic insights.

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“…Voronoi-tessellated Markovian milestoning is an implementation that allows reconstruction of the long-time dynamics of a system from independent simulations confined within a set of cells spanning the space of the reaction coordinates (9). This method has successfully captured the rates of CO entry/exit in myoglobin (10), and recently the ligand binding kinetics (11). Here, we make use of the "soft-walls" version, which confines the sampling within the Voronoi cells using flat-bottom harmonic restraining potentials (12).…”

Section: Introductionmentioning

confidence: 99%

Free energy and kinetics of cAMP permeation through connexin26 hemichannel with and without voltage

Jiang

Lin

Botello‐Smith

et al. 2021

Preprint

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The connexin family is a diverse group of highly regulated non-β-barrel wide-pore channels permeable to biological signaling molecules. Despite their critical roles in mediating selective molecular signaling in health and disease, the molecular basis of permeation through these pores remains unclear. Here, we report the thermodynamics and kinetics of binding and transport of a second messenger, adenosine-3’,5’-cyclophosphate (cAMP), through a connexin26 hemichannel. Inward and outward fluxes of cAMP were first obtained from 4 μs simulations with voltages and multiple cAMPs in solution. The results are compared with the intrinsic potential of mean force (PMF) and the mean first passage times (MFPTs) of a single cAMP in the absence of voltage, obtained from a total of 16.5 μs of multi-replica Voronoi-tessellated Markovian milestoning simulations. The computed transit times through the pore correspond well to existing experimental data. Both voltage simulations and milestoning simulations revealed two cAMP binding sites with binding constants and dissociation rates computed from PMF and MFPTs. The protein dipole inside the pore produces an asymmetric PMF, reflected in unequal cAMP MFPTs in each direction once within the pore. The free energy profiles under voltages derived from intrinsic PMF provided a unified understanding of directional transition rates with/without voltage, and revealed the unique role of channel polarity and the mobile electrolyte within a wide pore on the total free energy. In addition, we show how these factors influence the cAMP dipole vector during permeation, and how cAMP affects the local and non-local pore diameter in a position-dependent manner.Significance StatementConnexins are wide-pore channels permeable to cellular signaling molecules. They mediate molecular signaling crucial in physiology, pathology, and development; mutations in connexins cause human pathologies. However, the fundamental structural, thermodynamic, and kinetic determinants of molecular permeability properties are unknown. Using multiple molecular dynamics simulation techniques, we report, for the first time, an in-depth investigation of the free energy and the directional transition rates of an important biological signaling molecule, cAMP, through a connexin channel. We reveal the energetics and binding sites that determine the cAMP flux, and the effects of mobile ions and external electrical field on the process. The results provide a basis for understanding the unique features of molecular flux through connexins and other non-β-barrel wide-pore channels.

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Predicting Ligand Binding Kinetics Using a Markovian Milestoning with Voronoi Tessellations Multiscale Approach

Cited by 11 publications

References 0 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

Protein flexibility and dissociation pathway differentiation can explain onset of resistance mutations in kinases

Free energy and kinetics of cAMP permeation through connexin26 hemichannel with and without voltage

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