Memetic algorithms for ligand expulsion from protein cavities

Rydzewski, Jakub; Nowak, Wiesław

doi:10.1063/1.4931181

Cited by 26 publications

(41 citation statements)

References 73 publications

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“…The RPs of the hupA dissociation were computed using MS, an enhanced-sampling method to probe ligand dissociation from the active site of an enzyme to solvent. 21,24 The method constructs all possible heterogeneous RPs along transient tunnels without initial guesses of intermediate or final states, requiring only crystallographic information. An initial guess of the trajectory R(t) joining R A and R B (Figure 1) was determined by minimizing the effective interaction energy Λ between hupA and the enzyme…”

Section: IImentioning

confidence: 99%

Kinetics of Huperzine A Dissociation from Acetylcholinesterase via Multiple Unbinding Pathways

Rydzewski

Jakubowski

Nowak

et al. 2018

J. Chem. Theory Comput.

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The dissociation of huperzine A (hupA) from Torpedo californica acetylcholinesterase ( TcAChE) was investigated by 4 μs unbiased and biased all-atom molecular dynamics (MD) simulations in explicit solvent. We performed our study using memetic sampling (MS) for the determination of reaction pathways (RPs), metadynamics to calculate free energy, and maximum-likelihood estimation (MLE) to recover kinetic rates from unbiased MD simulations. Our simulations suggest that the dissociation of hupA occurs mainly via two RPs: a front door along the axis of the active-site gorge (pwf) and through a new transient side door (pws), i.e., formed by the Ω-loop (residues 67-94 of TcAChE). An analysis of the inhibitor unbinding along the RPs suggests that pws is opened transiently after hupA and the Ω-loop reach a low free-energy transition state characterized by the orientation of the pyridone group of the inhibitor directed toward the Ω-loop plane. Unlike pws, pwf does not require large structural changes in TcAChE to be accessible. The estimated free energies and rates agree well with available experimental data. The dissociation rates along the unbinding pathways are similar, suggesting that the dissociation of hupA along pws is likely to be relevant. This indicates that perturbations to hupA- TcAChE interactions could potentially induce pathway hopping. In summary, our results characterize the slow-onset inhibition of TcAChE by hupA, which may provide the structural and energetic bases for the rational design of the next-generation slow-onset inhibitors with optimized pharmacokinetic properties for the treatment of Alzheimer's disease.

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Section: IImentioning

confidence: 99%

Kinetics of Huperzine A Dissociation from Acetylcholinesterase via Multiple Unbinding Pathways

Rydzewski

Jakubowski

Nowak

et al. 2018

J. Chem. Theory Comput.

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“…Nonetheless, as the ligand did not egress during unbiased MD, we evaluated whether modified RAMD could be useful to explore the effect the GluN2B‐E413G and other mutations on ligand egress. During channel‐exploration MD, it is normal to adjust the amount of acceleration on the ligand to a value that is appropriate for the ligand and protein . This was also the case for glutamate egress from GluN2B.…”

Section: Discussionmentioning

confidence: 99%

The GluN2B‐Glu413Gly NMDA receptor variant arising from a de novo GRIN2B mutation promotes ligand‐unbinding and domain opening

et al. 2018

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N-methyl-D-aspartate (NMDA) receptors are transmembrane glutamate-binding ion channels that mediate neurotransmission in mammals. NMDA receptor subunits are tetrameric complexes of GluN1 and GluN2A-D subunits, encoded by the GRIN gene family. Of these subunits, GluN2B is suggested to be required for normal development of the central nervous system. A mutation identified in a patient with developmental delay, E413G, resides in the GluN2B ligand-binding domain and substantially reduces glutamate potency by an unknown mechanism. GluN2B Gly413, though near the agonist, is not in van der Waals contact with glutamate. Visual analysis of the GluN2B structure with the E413G mutation modeled suggests that replacement of Glu with Gly at this position increases solvent access to the ligand-binding domain. This was confirmed by molecular modeling, which showed that the ligand is more mobile in GluN2B-E413G than WT GluN2B. Evaluation of agonist occupancy using random accelerated molecular dynamics (RAMD) simulations predicts that the glutamate exits the binding-site more rapidly for GluN2B-E413G than WT receptors. This analysis was extended to other binding-site mutations, which produced qualitative agreement between experimentally determined EC values, deactivation time constants, and ligand motion within the binding-site. Furthermore, long sub-microsecond molecular dynamics simulations of the bi-lobed ligand-binding domain revealed that it adopted a cleft-open ligand-free state more often for GluN2B-E413G than wild-type GluN2B. This is consistent with the idea that L-glutamate binding is altered such that the ligand-binding domain occupies the open-cleft conformation associated with the closed channel.

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“…Compared with SMD, RaMD requires no predefinition of ligand dissociation pathway and thus enables detecting alternative ligand release pathway. However, careful selections of the force magnitude and threshold distance that are used to determine whether the force direction should be changed, are still needed [108]. Improper selection of force might lead to unexpected conformational changes in protein structure, and specific parameters should be set for different biomolecules [109−111].…”

Section: Random Acceleration Molecular Dynamicsmentioning

confidence: 99%

Advances in enhanced sampling molecular dynamics simulations for biomolecules

Wang

Zhang

2019

Chinese Journal of Chemical Physics

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Molecular dynamics simulation has emerged as a powerful computational tool for studying biomolecules as it can provide atomic insights into the conformational transitions involved in biological functions. However, when applied to complex biological macromolecules, the conformational sampling ability of conventional molecular dynamics is limited by the rugged free energy landscapes, leading to inherent timescale gaps between molecular dynamics simulations and real biological processes. To address this issue, several advanced enhanced sampling methods have been proposed to improve the sampling efficiency in molecular dynamics. In this review, the theoretical basis, practical applications, and recent improvements of both constraint and unconstrained enhanced sampling methods are summarized. Furthermore, the combined utilizations of different enhanced sampling methods that take advantage of both approaches are also briefly discussed.

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Memetic algorithms for ligand expulsion from protein cavities

Cited by 26 publications

References 73 publications

Kinetics of Huperzine A Dissociation from Acetylcholinesterase via Multiple Unbinding Pathways

Kinetics of Huperzine A Dissociation from Acetylcholinesterase via Multiple Unbinding Pathways

The GluN2B‐Glu413Gly NMDA receptor variant arising from a de novo GRIN2B mutation promotes ligand‐unbinding and domain opening

Advances in enhanced sampling molecular dynamics simulations for biomolecules

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