scholarly journals Simulating the dynamics of the mechanochemical cycle of myosin-V

2017 ◽  
Vol 114 (9) ◽  
pp. 2259-2264 ◽  
Author(s):  
Shayantani Mukherjee ◽  
Raphael Alhadeff ◽  
Arieh Warshel
Keyword(s):  
Molecular Motors ◽  
Energy Landscapes ◽  
Myosin V ◽  
Hand Motion ◽  
Directional Motion ◽  
Velocity Characteristic ◽  
Force Velocity ◽  
Stall Force ◽  
Mechanochemical Cycle ◽  
Rate Limiting

The detailed dynamics of the cycle of myosin-V are explored by simulation approaches, examining the nature of the energy-driven motion. Our study started with Langevin dynamics (LD) simulations on a very coarse landscape with a single rate-limiting barrier and reproduced the stall force and the hand-over-hand dynamics. We then considered a more realistic landscape and used time-dependent Monte Carlo (MC) simulations that allowed trajectories long enough to reproduce the force/velocity characteristic sigmoidal correlation, while also reproducing the hand-over-hand motion. Overall, our study indicated that the notion of a downhill lever-up to lever-down process (popularly known as the powerstroke mechanism) is the result of the energetics of the complete myosin-V cycle and is not the source of directional motion or force generation on its own. The present work further emphasizes the need to use well-defined energy landscapes in studying molecular motors in general and myosin in particular.

scholarly journals Reexamining the origin of the directionality of myosin V

2017 ◽  
Vol 114 (39) ◽  
pp. 10426-10431 ◽  
Author(s):  
Raphael Alhadeff ◽  
Arieh Warshel
Keyword(s):  
Kinetic Equations ◽  
Experimental Information ◽  
Power Stroke ◽  
Myosin V ◽  
Time Resolved ◽  
Directional Motion ◽  
Long Time ◽  
Adp Release ◽  
Rate Limiting ◽  
Binding Energy Calculations

The nature of the conversion of chemical energy to directional motion in myosin V is examined by careful simulations that include two complementary methods: direct Langevin Dynamics (LD) simulations with a scaled-down potential that provided a detailed time-resolved mechanism, and kinetic equations solution for the ensemble long-time propagation (based on information collected for segments of the landscape using LD simulations and experimental information). It is found that the directionality is due to the rate-limiting ADP release step rather than the potential energy of the lever arm angle. We show that the energy of the power stroke and the barriers involved in it are of minor consequence to the selectivity of forward over backward steps and instead suggest that the selective release of ADP from a postrigor myosin motor head promotes highly selective and processive myosin V. Our model is supported by different computational methods—LD simulations, Monte Carlo simulations, and kinetic equations solution—as well as by structure-based binding energy calculations.

scholarly journals Kinetics and Thermodynamics of the Rate Limiting Conformational Change in the Myosin V Mechanochemical Cycle

2011 ◽  
Vol 100 (3) ◽  
pp. 117a
Author(s):  
Donald J. Jacobs ◽  
Darshan Trivedi ◽  
Charles C. David ◽  
Christopher M. Yengo
Keyword(s):  
Conformational Change ◽  
Myosin V ◽  
Kinetics And Thermodynamics ◽  
Mechanochemical Cycle ◽  
Rate Limiting

scholarly journals 2P130 Dynamic cooperative binding of myosin V on actin filament(Molecular motors,Poster Presentations)

2007 ◽  
Vol 47 (supplement) ◽  
pp. S145
Author(s):  
Jun Kozuka ◽  
Yoshiharu Ishii ◽  
Toshio Yanagida
Keyword(s):  
Actin Filament ◽  
Molecular Motors ◽  
Cooperative Binding ◽  
Myosin V ◽  
Poster Presentations

scholarly journals The novel proteins Rng8 and Rng9 regulate the myosin-V Myo51 during fission yeast cytokinesis

2014 ◽  
Vol 205 (3) ◽  
pp. 357-375 ◽  
Author(s):  
Ning Wang ◽  
Libera Lo Presti ◽  
Yi-Hua Zhu ◽  
Minhee Kang ◽  
Zhengrong Wu ◽  
...  
Keyword(s):  
Fission Yeast ◽  
Molecular Motors ◽  
Coiled Coil ◽  
Myosin V ◽  
Contractile Ring ◽  
Novel Proteins ◽  
Ring Assembly ◽  
Actin Cables ◽  
Order Complexes

The myosin-V family of molecular motors is known to be under sophisticated regulation, but our knowledge of the roles and regulation of myosin-Vs in cytokinesis is limited. Here, we report that the myosin-V Myo51 affects contractile ring assembly and stability during fission yeast cytokinesis, and is regulated by two novel coiled-coil proteins, Rng8 and Rng9. Both rng8Δ and rng9Δ cells display similar defects as myo51Δ in cytokinesis. Rng8 and Rng9 are required for Myo51’s localizations to cytoplasmic puncta, actin cables, and the contractile ring. Myo51 puncta contain multiple Myo51 molecules and walk continuously on actin filaments in rng8+ cells, whereas Myo51 forms speckles containing only one dimer and does not move efficiently on actin tracks in rng8Δ. Consistently, Myo51 transports artificial cargos efficiently in vivo, and this activity is regulated by Rng8. Purified Rng8 and Rng9 form stable higher-order complexes. Collectively, we propose that Rng8 and Rng9 form oligomers and cluster multiple Myo51 dimers to regulate Myo51 localization and functions.

scholarly journals Cluster models of molecular motors: kinesin and myosin V

2014 ◽  
Vol 6 (5) ◽  
pp. 747-760
Author(s):  
V. P. Trifonenkov ◽  
A. V. Kargovsky
Keyword(s):  
Molecular Motors ◽  
Cluster Models ◽  
Myosin V

scholarly journals Stochastically pumped adaptation and directional motion of molecular machines

2018 ◽  
Vol 115 (38) ◽  
pp. 9405-9413 ◽  
Author(s):  
R. Dean Astumian
Keyword(s):  
Single Molecule ◽  
Molecular Motors ◽  
High Efficiency ◽  
Probability Distributions ◽  
Molecular Machines ◽  
High Energy ◽  
Stochastic Thermodynamics ◽  
Recent Developments ◽  
Directional Motion ◽  
External Fluctuations

Recent developments in synthetic molecular motors and pumps have sprung from a remarkable confluence of experiment and theory. Synthetic accomplishments have facilitated the ability to design and create molecules, many of them featuring mechanically bonded components, to carry out specific functions in their environment—walking along a polymeric track, unidirectional circling of one ring about another, synthesizing stereoisomers according to an external protocol, or pumping rings onto a long rod-like molecule to form and maintain high-energy, complex, nonequilibrium structures from simpler antecedents. Progress in the theory of nanoscale stochastic thermodynamics, specifically the generalization and extension of the principle of microscopic reversibility to the single-molecule regime, has enhanced the understanding of the design requirements for achieving strong unidirectional motion and high efficiency of these synthetic molecular machines for harnessing energy from external fluctuations to carry out mechanical and/or chemical functions in their environment. A key insight is that the interaction between the fluctuations and the transition state energies plays a central role in determining the steady-state concentrations. Kinetic asymmetry, a requirement for stochastic adaptation, occurs when there is an imbalance in the effect of the fluctuations on the forward and reverse rate constants. Because of strong viscosity, the motions of the machine can be viewed as mechanical equilibrium processes where mechanical resonances are simply impossible but where the probability distributions for the state occupancies and trajectories are very different from those that would be expected at thermodynamic equilibrium.

scholarly journals A mechanism for acetylcholine receptor gating based on structure, coupling, phi, and flip

2016 ◽  
Vol 149 (1) ◽  
pp. 85-103 ◽  
Author(s):  
Shaweta Gupta ◽  
Srirupa Chakraborty ◽  
Ridhima Vij ◽  
Anthony Auerbach
Keyword(s):  
Conformational Changes ◽  
Nicotinic Acetylcholine Receptors ◽  
Acetylcholine Receptors ◽  
Single Channel ◽  
Bubble Formation ◽  
Transmembrane Helix ◽  
Energy Landscapes ◽  
Rate Limiting Step ◽  
Sequence Domain ◽  
Rate Limiting

Nicotinic acetylcholine receptors are allosteric proteins that generate membrane currents by isomerizing (“gating”) between resting and active conformations under the influence of neurotransmitters. Here, to explore the mechanisms that link the transmitter-binding sites (TBSs) with the distant gate, we use mutant cycle analyses to measure coupling between residue pairs, phi value analyses to sequence domain rearrangements, and current simulations to reproduce a microsecond shut component (“flip”) apparent in single-channel recordings. Significant interactions between amino acids separated by >15 Å are rare; an exception is between the αM2–M3 linkers and the TBSs that are ∼30 Å apart. Linker residues also make significant, local interactions within and between subunits. Phi value analyses indicate that without agonists, the linker is the first region in the protein to reach the gating transition state. Together, the phi pattern and flip component suggest that a complete, resting↔active allosteric transition involves passage through four brief intermediate states, with brief shut events arising from sojourns in all or a subset. We derive energy landscapes for gating with and without agonists, and propose a structure-based model in which resting→active starts with spontaneous rearrangements of the M2–M3 linkers and TBSs. These conformational changes stabilize a twisted extracellular domain to promote transmembrane helix tilting, gate dilation, and the formation of a “bubble” that collapses to initiate ion conduction. The energy landscapes suggest that twisting is the most energetically unfavorable step in the resting→active conformational change and that the rate-limiting step in the reverse process is bubble formation.

scholarly journals 2P133 Actin gliding over myosin V S1 tethered on a glass surface at the head domain(Molecular motors,Oral Presentations)

2007 ◽  
Vol 47 (supplement) ◽  
pp. S146
Author(s):  
Naoki Nagura ◽  
Yuta Saito ◽  
Yusuke Tanaka ◽  
Toshio Ando
Keyword(s):  
Molecular Motors ◽  
Glass Surface ◽  
Myosin V ◽  
Head Domain ◽  
Oral Presentations

scholarly journals Secretory vesicle transport velocity in living cells depends on the myosin-V lever arm length

2002 ◽  
Vol 156 (1) ◽  
pp. 35-40 ◽  
Author(s):  
Daniel H. Schott ◽  
Ruth N. Collins ◽  
Anthony Bretscher
Keyword(s):  
Molecular Motors ◽  
Secretory Vesicle ◽  
Genetically Engineered ◽  
Secretory Vesicles ◽  
Myosin V ◽  
Lever Arm ◽  
Wide Range ◽  
Transport Velocity ◽  
Maximal Speed ◽  
Muscle Myosin

Myosins are molecular motors that exert force against actin filaments. One widely conserved myosin class, the myosin-Vs, recruits organelles to polarized sites in animal and fungal cells. However, it has been unclear whether myosin-Vs actively transport organelles, and whether the recently challenged lever arm model developed for muscle myosin applies to myosin-Vs. Here we demonstrate in living, intact yeast that secretory vesicles move rapidly toward their site of exocytosis. The maximal speed varies linearly over a wide range of lever arm lengths genetically engineered into the myosin-V heavy chain encoded by the MYO2 gene. Thus, secretory vesicle polarization is achieved through active transport by a myosin-V, and the motor mechanism is consistent with the lever arm model.

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