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Molecular Motors: Mechanical Properties and Regulation

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A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Biophysics".

Deadline for manuscript submissions: closed (30 April 2023) | Viewed by 11052

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Prof. Dr. Massimo Reconditi

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Guest Editor

Department of Experimental and Clinical Medicine, University of Florence, 50134 Florence, Italy
Interests: muscle physiology; mathematical modelling of muscle contraction; mechanics and structure of molecular motors
Special Issues, Collections and Topics in MDPI journals

Dr. Marco Capitanio

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Guest Editor

1. Department of Physics and Astronomy, Università degli Studi di Firenze, 50019 Florence, Italy
2. LENS (European Laboratory for Non-linear Spectroscopy), 50019 Sesto Fiorentino, Italy
Interests: single molecule biophysics; molecular motors; mechanobiology
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Molecular motors, or motor proteins, transform chemical energy into mechanical output. Because of their many fundamental biological functions, molecular motors are ubiquitous in living cells. To cover but a few of their functions, they are responsible for cell movement and division and driving intracellular trafficking inside the cell, and they may work cooperatively to produce macroscopic outputs such as in muscle contraction or bending movement in flagella and cilia.

In the last 25 years, different techniques have been developed to allow the study of the mechanical properties and action of molecular motors at the level of the single molecule, both in vitro and in situ. More recently, interest is increasing in the regulation of their activity to accomplish their physiological tasks. Despite the significant advances which have occurred in recent years, the fundamental mechanisms of their functioning are still not fully understood.

The aim of this Special Issue is to bring together reviews and original papers on the mechanics of the different classes of molecular motors, the relation with their structure, and their action and regulation inside the cell.

From an experimental point of view, novel or refined techniques and analyses that make it possible to uncover new mechanisms of motor protein function and their role in health and disease will be of particular interest. From a modelling point of view, models accounting for the cooperative action of multiple motors and their mechanical and biochemical regulation will be particularly valuable.

Prof. Dr. Massimo Reconditi
Prof. Dr. Marco Capitanio
Guest Editors

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Published Papers (6 papers)

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Research

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17 pages, 2230 KiB

Open AccessArticle

Myosin Isoform-Dependent Effect of Omecamtiv Mecarbil on the Regulation of Force Generation in Human Cardiac Muscle

by Beatrice Scellini, Nicoletta Piroddi, Marica Dente, J. Manuel Pioner, Cecilia Ferrantini, Corrado Poggesi and Chiara Tesi

Int. J. Mol. Sci. 2024, 25(18), 9784; https://doi.org/10.3390/ijms25189784 - 10 Sep 2024

Viewed by 706

Abstract

Omecamtiv mecarbil (OM) is a small molecule that has been shown to improve the function of the slow human ventricular myosin (MyHC) motor through a complex perturbation of the thin/thick filament regulatory state of the sarcomere mediated by binding to myosin allosteric sites coupled to inorganic phosphate (Pi) release. Here, myofibrils from samples of human left ventricle (β-slow MyHC-7) and left atrium (α-fast MyHC-6) from healthy donors were used to study the differential effects of μmolar [OM] on isometric force in relaxing conditions (pCa 9.0) and at maximal (pCa 4.5) or half-maximal (pCa 5.75) calcium activation, both under control conditions (15 °C; equimolar DMSO; contaminant inorganic phosphate [Pi] ~170 μM) and in the presence of 5 mM [Pi]. The activation state and OM concentration within the contractile lattice were rapidly altered by fast solution switching, demonstrating that the effect of OM was rapid and fully reversible with dose-dependent and myosin isoform-dependent features. In MyHC-7 ventricular myofibrils, OM increased submaximal and maximal Ca²⁺-activated isometric force with a complex dose-dependent effect peaking (40% increase) at 0.5 μM, whereas in MyHC-6 atrial myofibrils, it had no effect or—at concentrations above 5 µM—decreased the maximum Ca²⁺-activated force. In both ventricular and atrial myofibrils, OM strongly depressed the kinetics of force development and relaxation up to 90% at 10 μM [OM] and reduced the inhibition of force by inorganic phosphate. Interestingly, in the ventricle, but not in the atrium, OM induced a large dose-dependent Ca²⁺-independent force development and an increase in basal ATPase that were abolished by the presence of millimolar inorganic phosphate, consistent with the hypothesis that the widely reported Ca²⁺-sensitising effect of OM may be coupled to a change in the state of the thick filaments that resembles the on–off regulation of thin filaments by Ca²⁺. The complexity of this scenario may help to understand the disappointing results of clinical trials testing OM as inotropic support in systolic heart failure compared with currently available inotropic drugs that alter the calcium signalling cascade. Full article

(This article belongs to the Special Issue Molecular Motors: Mechanical Properties and Regulation)

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13 pages, 1104 KiB

Open AccessArticle

Waiting Time Distributions in Hybrid Models of Motor–Bead Assays: A Concept and Tool for Inference

by Benjamin Ertel, Jann van der Meer and Udo Seifert

Int. J. Mol. Sci. 2023, 24(8), 7610; https://doi.org/10.3390/ijms24087610 - 20 Apr 2023

Cited by 2 | Viewed by 1458

Abstract

In single-molecule experiments, the dynamics of molecular motors are often observed indirectly by measuring the trajectory of an attached bead in a motor–bead assay. In this work, we propose a method to extract the step size and stalling force for a molecular motor without relying on external control parameters. We discuss this method for a generic hybrid model that describes bead and motor via continuous and discrete degrees of freedom, respectively. Our deductions are solely based on the observation of waiting times and transition statistics of the observable bead trajectory. Thus, the method is non-invasive, operationally accessible in experiments and can, in principle, be applied to any model describing the dynamics of molecular motors. We briefly discuss the relation of our results to recent advances in stochastic thermodynamics on inference from observable transitions. Our results are confirmed by extensive numerical simulations for parameters values of an experimentally realized F1-ATPase assay. Full article

(This article belongs to the Special Issue Molecular Motors: Mechanical Properties and Regulation)

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16 pages, 6238 KiB

Open AccessCommunication

Molecular Dynamics Assessment of Mechanical Properties of the Thin Filaments in Cardiac Muscle

by Natalia A. Koubassova and Andrey K. Tsaturyan

Int. J. Mol. Sci. 2023, 24(5), 4792; https://doi.org/10.3390/ijms24054792 - 1 Mar 2023

Cited by 3 | Viewed by 1788

Abstract

Contraction of cardiac muscle is regulated by Ca

^{2 +}

ions via regulatory proteins, troponin (Tn), and tropomyosin (Tpm) associated with the thin (actin) filaments in myocardial sarcomeres. The binding of Ca

^{2 +}

to a Tn subunit causes mechanical and structural changes [...] Read more.

Contraction of cardiac muscle is regulated by Ca

^{2 +}

ions via regulatory proteins, troponin (Tn), and tropomyosin (Tpm) associated with the thin (actin) filaments in myocardial sarcomeres. The binding of Ca

^{2 +}

to a Tn subunit causes mechanical and structural changes in the multiprotein regulatory complex. Recent cryo-electron microscopy (cryo-EM) models of the complex allow one to study the dynamic and mechanical properties of the complex using molecular dynamics (MD). Here we describe two refined models of the thin filament in the calcium-free state that include protein fragments unresolved by cryo-EM and reconstructed using structure prediction software. The parameters of the actin helix and the bending, longitudinal, and torsional stiffness of the filaments estimated from the MD simulations performed with these models were close to those found experimentally. However, problems revealed from the MD simulation suggest that the models require further refinement by improving the protein–protein interaction in some regions of the complex. The use of relatively long refined models of the regulatory complex of the thin filament allows one to perform MD simulation of the molecular mechanism of Ca

^{2 +}

regulation of contraction without additional constraints and study the effects of cardiomyopathy-associated mutation of the thin filament proteins of cardiac muscle. Full article

(This article belongs to the Special Issue Molecular Motors: Mechanical Properties and Regulation)

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27 pages, 3155 KiB

Open AccessArticle

Insights into Muscle Contraction Derived from the Effects of Small-Molecular Actomyosin-Modulating Compounds

by Alf Månsson and Dilson E. Rassier

Int. J. Mol. Sci. 2022, 23(20), 12084; https://doi.org/10.3390/ijms232012084 - 11 Oct 2022

Cited by 1 | Viewed by 1501

Abstract

Bottom-up mechanokinetic models predict ensemble function of actin and myosin based on parameter values derived from studies using isolated proteins. To be generally useful, e.g., to analyze disease effects, such models must also be able to predict ensemble function when actomyosin interaction kinetics are modified differently from normal. Here, we test this capability for a model recently shown to predict several physiological phenomena along with the effects of the small molecular compound blebbistatin. We demonstrate that this model also qualitatively predicts effects of other well-characterized drugs as well as varied concentrations of MgATP. However, the effects of one compound, amrinone, are not well accounted for quantitatively. We therefore systematically varied key model parameters to address this issue, leading to the increased amplitude of the second sub-stroke of the power stroke from 1 nm to 2.2 nm, an unchanged first sub-stroke (5.3–5.5 nm), and an effective cross-bridge attachment rate that more than doubled. In addition to better accounting for the effects of amrinone, the modified model also accounts well for normal physiological ensemble function. Moreover, a Monte Carlo simulation-based version of the model was used to evaluate force–velocity data from small myosin ensembles. We discuss our findings in relation to key aspects of actin–myosin operation mechanisms causing a non-hyperbolic shape of the force–velocity relationship at high loads. We also discuss remaining limitations of the model, including uncertainty of whether the cross-bridge elasticity is linear or not, the capability to account for contractile properties of very small actomyosin ensembles (<20 myosin heads), and the mechanism for requirements of a higher cross-bridge attachment rate during shortening compared to during isometric contraction. Full article

(This article belongs to the Special Issue Molecular Motors: Mechanical Properties and Regulation)

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14 pages, 1767 KiB

Open AccessArticle

Anisotropic Elasticity of the Myosin Motor in Muscle

by Marco Caremani and Massimo Reconditi

Int. J. Mol. Sci. 2022, 23(5), 2566; https://doi.org/10.3390/ijms23052566 - 25 Feb 2022

Cited by 1 | Viewed by 1852

Abstract

To define the mechanics and energetics of the myosin motor action in muscles, it is mandatory to know fundamental parameters such as the stiffness and the force of the single myosin motor, and the fraction of motors attached during contraction. These parameters can be defined in situ using sarcomere−level mechanics in single muscle fibers under the assumption that the stiffness of a myosin dimer with both motors attached (as occurs in rigor, when all motors are attached) is twice that of a single motor (as occurs in the isometric contraction). We use a mechanical/structural model to identify the constraints that underpin the stiffness of the myosin dimer with both motors attached to actin. By comparing the results of the model with the data in the literature, we conclude that the two-fold axial stiffness of the dimers with both motors attached is justified by a stiffness of the myosin motor that is anisotropic and higher along the axis of the myofilaments. A lower azimuthal stiffness of the motor plays an important role in the complex architecture of the sarcomere by allowing the motors to attach to actin filaments at different azimuthal angles relative to the thick filament. Full article

(This article belongs to the Special Issue Molecular Motors: Mechanical Properties and Regulation)

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Review

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24 pages, 2061 KiB

Open AccessReview

Muscle Mechanics and Thick Filament Activation: An Emerging Two-Way Interaction for the Vertebrate Striated Muscle Fine Regulation

by Lorenzo Marcucci

Int. J. Mol. Sci. 2023, 24(7), 6265; https://doi.org/10.3390/ijms24076265 - 27 Mar 2023

Cited by 5 | Viewed by 2688

Abstract

Contraction in striated muscle is classically described as regulated by calcium-mediated structural changes in the actin-containing thin filaments, which release the binding sites for the interaction with myosin motors to produce force. In this view, myosin motors, arranged in the thick filaments, are basically always ready to interact with the thin filaments, which ultimately regulate the contraction. However, a new “dual-filament” activation paradigm is emerging, where both filaments must be activated to generate force. Growing evidence from the literature shows that the thick filament activation has a role on the striated muscle fine regulation, and its impairment is associated with severe pathologies. This review is focused on the proposed mechanical feedback that activates the inactive motors depending on the level of tension generated by the active ones, the so-called mechanosensing mechanism. Since the main muscle function is to generate mechanical work, the implications on muscle mechanics will be highlighted, showing: (i) how non-mechanical modulation of the thick filament activation influences the contraction, (ii) how the contraction influences the activation of the thick filament and (iii) how muscle, through the mechanical modulation of the thick filament activation, can regulate its own mechanics. This description highlights the crucial role of the emerging bi-directional feedback on muscle mechanical performance. Full article

(This article belongs to the Special Issue Molecular Motors: Mechanical Properties and Regulation)

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