Early stages of the recovery stroke in myosin II studied by molecular dynamics simulations

Baumketner, Andrij; Nesmelov, Yuri E.

doi:10.1002/pro.737

Cited by 14 publications

(17 citation statements)

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“…Implicit solvent simulations of large proteins using these models may run even slower than the corresponding simulations in explicit solvent. 25 An alternative to the physics-based solvation free energy is statistical potentials. 26 Instead of providing a universal solvation model that fits all proteins, these potentials are derived specifically for the given system of interest and depend on its thermodynamic state.…”

Section: Introductionmentioning

confidence: 99%

Reduced atomic pair-interaction design (RAPID) model for simulations of proteins

Baumketner

2013

The Journal of Chemical Physics

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Increasingly, theoretical studies of proteins focus on large systems. This trend demands the development of computational models that are fast, to overcome the growing complexity, and accurate, to capture the physically relevant features. To address this demand, we introduce a protein model that uses all-atom architecture to ensure the highest level of chemical detail while employing effective pair potentials to represent the effect of solvent to achieve the maximum speed. The effective potentials are derived for amino acid residues based on the condition that the solvent-free model matches the relevant pair-distribution functions observed in explicit solvent simulations. As a test, the model is applied to alanine polypeptides. For the chain with 10 amino acid residues, the model is found to reproduce properly the native state and its population. Small discrepancies are observed for other folding properties and can be attributed to the approximations inherent in the model. The transferability of the generated effective potentials is investigated in simulations of a longer peptide with 25 residues. A minimal set of potentials is identified that leads to qualitatively correct results in comparison with the explicit solvent simulations. Further tests, conducted for multiple peptide chains, show that the transferable model correctly reproduces the experimentally observed tendency of polyalanines to aggregate into β-sheets more strongly with the growing length of the peptide chain. Taken together, the reported results suggest that the proposed model could be used to succesfully simulate folding and aggregation of small peptides in atomic detail. Further tests are needed to assess the strengths and limitations of the model more thoroughly.

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Section: Introductionmentioning

confidence: 99%

Reduced atomic pair-interaction design (RAPID) model for simulations of proteins

Baumketner

2013

The Journal of Chemical Physics

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“…Computational studies by our group14 and by others15, 16 suggest that the closure of Switch II occurs early on in the reaction, triggering the deformation of the relay helix and the rotation of the converter domain. The two events occur in physically distinct locations, separated one from another by close to 40 Å.…”

Section: Introductionmentioning

confidence: 78%

“…We note that a correlation between SH1 and the converter domain does not necessarily imply a causative link between them. Here, one can envision three scenarios by which the signal from the active site, where the closing of Switch II triggers the recovery stroke,14–16 is propagated to the force‐generating region. First, the signal travels directly to the relay helix through its amino terminal that interacts with the Switch II loop.…”

Section: Discussionmentioning

confidence: 99%

“…The rotation and the closure of the Switch II in this18 and similar models15 are fully correlated, with the implication that one cannot be realized without the other. This mechanistic view is questioned in statistical models of the coupling,14, 16, 19, 20 where the open/close state of the switch favors statistically M */ M ** conformation of the relay helix but does not define it in a deterministic manner. As a result, the switch and the converter/relay helix assembly communicate with one another via the shift of population mechanism, rather than by mechanistic pathways.…”

Section: Introductionmentioning

confidence: 99%

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Interactions between relay helix and Src homology 1 (SH1) domain helix drive the converter domain rotation during the recovery stroke of myosin II

Baumketner

2012

Proteins

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Myosin motor protein exists in two alternative conformations, pre-recovery state M* and post-recovery state M**, upon ATP binding. The details of the M*-to-M** transition, known as the recovery stroke to reflect its role as the functional opposite of the force-generating power stroke, remain elusive. The defining feature of the post-recovery state is a kink in the relay helix, a key part of the protein involved in force generation. In this paper we determine the interactions that are responsible for the appearance of the kink. We design a series of computational models that contain three other segments, relay loop, converter domain and Src homology 1 domain helix (SH1), with which relay helix interacts, and determine their structure in accurate replica exchange molecular dynamics simulations in explicit solvent. By conducting an exhaustive combinatorial search among different models we find that: 1) the converter domain must be attached to the relay helix during the transition, so it does not interfere with other parts of the protein, 2) the structure of the relay helix is controlled by SH1 helix. The kink is strongly coupled to the position of SH1 helix. It arises as a result of direct interactions between SH1 and the relay helix and leads to a rotation of the C-terminal part of the relay helix which is subsequently transmitted to the converter domain.

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“…Previous computational works have focused so far on the effect of nucleotide [32] or actin binding [33] on myosin dynamics, the interactions between actin and myosin [34], the release of Pi [35], the modelling of the recovery stroke [36][37][38][39] or in general of the coupling between the actin binding site, the nucleotide binding site and the converter [40][41][42][43]. A significant part of these studies used enhanced sampling techniques to accelerate the transitions between the different states in the actomyosin cycle [35, 36, 38-41, 43, 44], while unbiased simulations with length > = 50 ns have been performed only recently [32,33,37,45] thanks to the increase of the available computational power.…”

Section: Discussionmentioning

confidence: 99%

Allosteric Modulation of Cardiac Myosin Dynamics by Omecamtiv Mecarbil

Hashem

Tiberti

Fornili

2018

Biophysical Journal

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New promising avenues for the pharmacological treatment of skeletal and heart muscle diseases rely on direct sarcomeric modulators, which are molecules that can directly bind to sarcomeric proteins and either inhibit or enhance their activity. A recent breakthrough has been the discovery of the myosin activator omecamtiv mecarbil (OM), which has been shown to increase the power output of the cardiac muscle and is currently in clinical trials for the treatment of heart failure. While the overall effect of OM on the mechano-chemical cycle of myosin is to increase the fraction of myosin molecules in the sarcomere that are strongly bound to actin, the molecular basis of its action is still not completely clear. We present here a Molecular Dynamics study of the motor domain of human cardiac myosin bound to OM, where the effects of the drug on the dynamical properties of the protein are investigated for the first time with atomistic resolution. We found that OM has a double effect on myosin dynamics, inducing a) an increased coupling of the motions of the converter and lever arm subdomains to the rest of the protein and b) a rewiring of the network of dynamic correlations, which produces preferential communication pathways between the OM binding site and distant functional regions. The location of the residues responsible for these effects suggests possible strategies for the future development of improved drugs and the targeting of specific cardiomyopathy-related mutations. Author summaryCardiac myosin is a motor protein responsible for the contraction of the heart muscle. New strategies for the cure of heart diseases are currently being developed by using myosin modulators, which are small molecules that can interact with myosin and modify its activity. The advantage of this approach over traditional drugs is that by directly targeting cardiac myosin it is possible to have drugs with reduced side effects. Moreover, the availability of a spectrum of molecules to finely tune myosin to a desired level of activity opens the possibility to develop more precise and personalised drug therapies. In this work, we study a recently discovered activator of cardiac myosin, omecamtiv mecarbil, in order to understand its mechanism of action. In particular, we use Molecular Dynamics simulations to unravel the effects of the drug on myosin motions, which are closely related to its PLOS Computational Biology | https://doi

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Early stages of the recovery stroke in myosin II studied by molecular dynamics simulations

Cited by 14 publications

References 46 publications

Reduced atomic pair-interaction design (RAPID) model for simulations of proteins

Reduced atomic pair-interaction design (RAPID) model for simulations of proteins

Interactions between relay helix and Src homology 1 (SH1) domain helix drive the converter domain rotation during the recovery stroke of myosin II

Allosteric Modulation of Cardiac Myosin Dynamics by Omecamtiv Mecarbil

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