Design principles governing the motility of myosin V

Hinczewski, Michael; Tehver, Riina; Thirumalai, D.

doi:10.1073/pnas.1312393110

Cited by 48 publications

(61 citation statements)

References 53 publications

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“…In brief, the MC simulations used a simplified myosin-V protein composed of three particles (two particles represent the two heads, and another joint particle represents their connection) moving along an actin filament. The use of only three particles is consistent with the important finding of Hinczewski et al (12) that the arms behave as rigid rods. Additionally, we performed some calculations in a kinetic MC model, where the energy states (minima and maxima) from Fig.…”

Section: Introductionsupporting

confidence: 87%

“…In addition, crucial information has been gained on the kinetics of the chemical and ligand-binding/release steps that make up the complete cycle. Based on this experimental information, several theoretical modeling studies (8)(9)(10)(11)(12)(13)(14)(15)(16)(17) explored the mechanochemical cycle, mostly using phenomenological modeling approaches, accompanied by some structure-based studies. One of the key ingredients used (almost always) in describing the unidirectionality and behavior under force in myosin-V is the nature of the conformational change, known as the powerstroke (PS), which is generally assumed to generate the force on actin filaments (18)(19)(20).…”

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confidence: 99%

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Simulating the dynamics of the mechanochemical cycle of myosin-V

Mukherjee

Alhadeff

Warshel

2017

Proc. Natl. Acad. Sci. U.S.A.

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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 timedependent 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.M yosin constitutes a superfamily of molecular motors comprising both the nonprocessive single-headed motors that are efficient in generating force on the actin filaments (e.g., myosin-II) and highly processive double-headed motors that can transport cellular load using tracks laid out by the cytoskeletal actin filaments (e.g., myosin-V, myosin-VI) (1, 2). The generation of force and unidirectional motion in each of the myosin molecules predominantly comprises tightly coupled events involving (i) binding and hydrolysis of ATP, followed by release of the products ADP and inorganic phosphate (P i ), occurring at the nucleotide-binding domain; (ii) binding and release of actin through the actin-binding domain; and (iii) a large conformational change of the lever arm that generates mechanical motion. Although the basic mechanochemical cycle is conserved in all members of the myosin superfamily, the exact nature of the coupling between the above steps in myosins, which decides the force-generating and load-bearing characteristics of different members, is unknown (SI Background).Numerous experiments, including kinetics and thermodynamic studies (3), high-resolution structural studies (4), electron microscopy studies (5), atomic force microscopy (AFM), and singlemolecule experiments (2, 6, 7), have advanced our understanding of the action of the system. Although details about the dynamical nature of the myosin-V, along with a quantitative knowledge of the force-response, have been learned from single-molecule studies, the structural studies have provided us with an atomistic knowledge of the key conformational states involved during the cycle, namely, the lever-up (pre) and lever-down (post) states (Fig. S1). In addition, crucial information has been gained on the kinetics of the chemical and ligand-binding/release steps that make up the complete cycle. Based on this experimental information, several theoretical modeling studies (8-17) explored the mechanochemical cycle, mostly using phenomenological modeling approaches, accompanied by s...

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Section: Introductionsupporting

confidence: 87%

mentioning

confidence: 99%

Simulating the dynamics of the mechanochemical cycle of myosin-V

Mukherjee

Alhadeff

Warshel

2017

Proc. Natl. Acad. Sci. U.S.A.

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“…Effect of modifying motor structure on the transport properties as well as on the directionality and processivity of molecular motor has been of great interest because it provides glimpses into the design principle of a motor at molecular level [30,[33][34][35][36]. Here, we explore how modification to motor structure changes the efficiency of motor in terms of Q.…”

Section: Comparison Of Q Between Different Types Of Kinesinsmentioning

confidence: 99%

Energetic costs, precision, and efficiency of a biological motor in cargo transport

Hwang

Hyeon

2017

Preprint

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Molecular motors play key roles in organizing the interior of cells. An efficient motor in cargo transport would travel with a high speed and a minimal error in transport time (or distance) while consuming minimal amount of energy. The travel distance and its variance of motor are, however, physically constrained by energy consumption, the principle of which has recently been formulated into the thermodynamic uncertainty relation. Here, we reinterpret the uncertainty measure (Q) defined in the thermodynamic uncertainty relation such that a motor efficient in cargo transport is characterized with a small Q. Analyses on the motility data from several types of molecular motors show that Q is a nonmonotic function of ATP concentration and load (f ). For kinesin-1, Q is locally minimized at [ATP] ≈ 200 µM and f ≈ 4 pN. Remarkably, for the mutant with a longer neck-linker this local minimum vanishes, and the energetic cost to achieve the same precision as the wild-type increases significantly, which underscores the importance of molecular structure in transport properties. For the biological motors studied here, their value of Q is semi-optimized under the cellular condition ([ATP] ≈ 1 mM, f = 0 − 1 pN). We find that among the motors, kinesin-1 at single molecule level is the most efficient in cargo transport.Biological systems are in nonequilibrium steady states (NESS) in which the energy and material currents flow constantly in and out of the system. Subjected to incessant thermal and nonequilibrium fluctuations, cellular processes are inherently stochastic and error-prone. To minimize detrimentaion effects, cells are equipped with a plethora of energy-consuming error-correction mechanisms. Trade-off relations between the energetic cost and information processing are ubiquitous in cellular processes, and have been a recurring theme in biology for many decades [1? ? -4].A recent study by Barato and Seifert [5] has formulated a concise inequality known as the thermodynamic uncertainty relation, the trade-off between energy consumption and precision of an observable from dissipative processes in NESS. To be more explicit, the uncertainty measure Q, defined as a product between the energy consumption (heat dissipation, Q(t)) from an energy-driven process in the steady state and the squared relative error of an output observable X(t), 2 X (t) = δX 2 / X 2 , is constant. It has been further conjectured that for an arbitrary chemical network formulated by Markov jump processes Q cannot be smaller than 2k B T ,The measure Q quantifies the uncertainty of a dynamic process. The smaller the value of Q, the more regular and predictable is the trajectory generated from the process, rendering the output observable more precise. The proof and physical significance of this inequality have been discussed [5][6][7][8][9][10]. In the presence of large fluctuations inherent to cellular processes, harnessing energy into precise motion is critical for accuracy in cellular computation.The uncertainty measure Q can be used to assess the e...

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“…Apart from ingenious experimental studies that have been able to explore the mechanochemical cycle, there have been theoretical attempts to understand the processes using structure-based or phenomenological modeling approaches in myosin (14)(15)(16)(17)(18)(19)(20).…”

mentioning

confidence: 99%

“…Progress on this front seems to be more relevant to the central question rather than simulating the dynamical behavior of the different states of myosin, and at present we are not aware of any structure-based model that actually provided an interpretation of the directional motion of myosin [although phenomenological studies and kinetic modeling have been instructive (14,18,19)]. Exploring the structure/ energy relationship in myosin V presents major challenges, owing in part to the absence of high-quality structural information on all of the intermediate conformations and nucleotide/actinbound forms.…”

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confidence: 99%

Electrostatic origin of the unidirectionality of walking myosin V motors

Mukherjee

Warshel

2013

Proc. Natl. Acad. Sci. U.S.A.

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Understanding the basis for the action of myosin motors and related molecular machines requires a quantitative energy-based description of the overall functional cycle. Previous theoretical attempts to do so have provided interesting insights on parts of the cycle but could not generate a structure-based free energy landscape for the complete cycle of myosin. In particular, a nonphenomenological structure/energy-based understanding of the unidirectional motion is still missing. Here we use a coarse-grained model of myosin V and generate a structure-based free energy surface of the largest conformational change, namely the transition from the post-to prepowerstroke movement. We also couple the observed energetics of ligand binding/hydrolysis and product release to that of the conformational surface and reproduce the energetics of the complete mechanochemical cycle. It is found that the release in electrostatic free energy upon changing the conformation of the lever arm and the convertor domain from its postto prepowerstroke state provides the necessary energy to bias the system towards the unidirectional movement of myosin V on the actin filament. The free energy change of 11 kcal is also in the range of ∼2-3 pN, which is consistent with the experimentally observed stalling force required to stop the motor completely on its track. The conformational-chemical coupling generating a successful powerstroke cycle is believed to be conserved among most members of the myosin family, thus highlighting the importance of the previously unknown role of electrostatics free energy in guiding the functional cycle in other actin-based myosin motors.yosin constitutes a diverse class of molecular motors that perform mechanical work by producing movement on the actin filaments. These cellular machines tightly couple various steps of the ATP hydrolysis and product release cycle with mechanical force generation on actin and can therefore perform coordinated movements within the cell (1-3). Classical examples of myosin motors constitute the muscle protein that performs a single mechanical force generation cycle and then detaches from the actin filament. These molecules work in large numbers to produce a net directed movement of the actin during muscle contraction (2). Furthermore, living cells have used the basic functional cycle of myosin to generate several other members of the myosin family, some of which produce repetitive mechanochemical movements on the actin filaments. The most studied among these processive motors is myosin V, which is responsible for carrying cargo to different destinations using the intracellular network of actin filaments (4). At the heart of all types of myosin action is its ability to couple large conformational changes with ATP hydrolysis and actin binding/release cycles to eventually perform a unidirectional motion (3). Although some features of the cycle are well understood, one of the most intriguing remaining problems is to unravel the factors that allow myosin V to walk in only one direction toward...

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Design principles governing the motility of myosin V

Cited by 48 publications

References 53 publications

Simulating the dynamics of the mechanochemical cycle of myosin-V

Simulating the dynamics of the mechanochemical cycle of myosin-V

Energetic costs, precision, and efficiency of a biological motor in cargo transport

Electrostatic origin of the unidirectionality of walking myosin V motors

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