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Register a new userDiscrete- versus continuous-state descriptions of the F1-ATPase molecular motor
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A discrete-state model of the F1-ATPase molecular motor is developed which describes not only the dependences of the rotation and ATP consumption rates on the chemical concentrations of ATP, ADP, and inorganic phosphate, but also on mechanical control parameters such as the friction coefficient and the external torque. The dependence on these mechanical parameters is given to the discrete-state model by fitting its transition rates to the continuous-angle model of P. Gaspard and E. Gerritsma [J. Theor. Biol. 247 (2007) 672-686]. This discrete-state model describes the behavior of the F1 motor in the regime of tight coupling between mechanical motion and chemical reaction. In this way, kinetic and thermodynamic properties of the F1 motor are obtained such as the Michaelis-Menten dependence of the rotation and ATP consumption rates on ATP concentration and its extension in the presence of ADP and Pi, their dependences on friction and external torque, as well as the chemical and mechanical thermodynamic efficiencies.
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Transport of intracellular cargo is often mediated by teams of molecular motors that function in a chaotic environment and varying conditions. We show that the motors have unique steady state behavior which enables transport modalities that are robust. Under reduced ATP concentrations, multi-motor configurations are preferred over single motors. Higher load force drives motors to cluster, but very high loads compel them to separate in a manner that promotes immediate cargo movement once the load reduces. These inferences, backed by analytical guarantees, provide unique insights into the coordination strategies adopted by motors.
F1F0 ATP synthase (ATPase) either facilitates the synthesis of ATP in the mitochondrial membranes and bacterial inner membranes in a process driven by the proton moving force (pmf), or uses the energy from ATP hydrolysis to pump protons against the concentration gradient across the membrane. ATPase is composed of two rotary motors, F0 and F1, which generate the opposing rotation and compete for control of their shared central gamma-shaft. Here we present a self-consistent physical model of the F1 motor as a simplified two-state Brownian ratchet based on the asymmetry of torsional elastic energy of the coiled-coil gamma-shaft. This stochastic model unifies the physical description of linear and rotary motors and explains the stepped unidirectional rotation of the $gamma$-shaft, in agreement with the `binding-change ideas of Boyer. Substituting the model parameters, all independently known from recent experiments, our model quantitatively reproduces the ATPase operation, e.g. the `no-load angular velocity is ca. 400~rad/s anticlockwise at 4 mM ATP, in close agreement with experiment. Increasing the pmf torque exerted by F0 can slow, stop and overcome the torque generated by F1, switching from ATP hydrolysis to synthesis at a very low value of `stall torque. We discuss the matters of the motor efficiency, which is very low if calculated from the useful mechanical work it produces - but is quite high when the `useful outcome is measured in the number of H+ pushed against the chemical gradient in the F1 ATP-driven operation.
Intracellular transport is an essential function in eucaryotic cells, facilitated by motor proteins - proteins converting chemical energy into kinetic energy. It is known that motor proteins work in teams enabling unidirectional and bidirectional transport of intracellular cargo over long distances. Disruptions of the underlying transport mechanisms, often caused by mutations that alter single motor characteristics, are known to cause neurodegenerative diseases. For example, phosphorylation of kinesin motor domain at the serine residue is implicated in Huntingtons disease, with a recent study of phosphorylated and phosphomimetic serine residues indicating lowered single motor stalling forces. In this article we report the effects of mutations of this nature on transport properties of cargo carried by multiple wild-type and mutant motors. Results indicate that mutants with altered stall forces might determine the average velocity and run-length even when they are outnumbered by wild type motors in the ensemble. It is shown that mutants gain a competitive advantage and lead to an increase in expected run-length when load on the cargo is in the vicinity of the mutants stalling force or a multiple of its stalling force. A separate contribution of this article is the development of a semi-analytic method to analyze transport of cargo by multiple motors of multiple types. The technique determines transition rates between various relative configurations of motors carrying the cargo using the transition rates between various absolute configurations. This enables exact computation of average velocity and run-length. It can also be used to introduce alterations of various single motor parameters to model a mutation and to deduce effects of such alterations on the transport of a common cargo by multiple motors. Our method is easily implementable and we provide a software package for general use.
In cells and in vitro assays the number of motor proteins involved in biological transport processes is far from being unlimited. The cytoskeletal binding sites are in contact with the same finite reservoir of motors (either the cytosol or the flow chamber) and hence compete for recruiting the available motors, potentially depleting the reservoir and affecting cytoskeletal transport. In this work we provide a theoretical framework to study, analytically and numerically, how motor density profiles and crowding along cytoskeletal filaments depend on the competition of motors for their binding sites. We propose two models in which finite processive motor proteins actively advance along cytoskeletal filaments and are continuously exchanged with the motor pool. We first look at homogeneous reservoirs and then examine the effects of free motor diffusion in the surrounding medium. We consider as a reference situation recent in vitro experimental setups of kinesin-8 motors binding and moving along microtubule filaments in a flow chamber. We investigate how the crowding of linear motor proteins moving on a filament can be regulated by the balance between supply (concentration of motor proteins in the flow chamber) and demand (total number of polymerised tubulin heterodimers). We present analytical results for the density profiles of bound motors, the reservoir depletion, and propose novel phase diagrams that present the formation of jams of motor proteins on the filament as a function of two tuneable experimental parameters: the motor protein concentration and the concentration of tubulins polymerized into cytoskeletal filaments. Extensive numerical simulations corroborate the analytical results for parameters in the experimental range and also address the effects of diffusion of motor proteins in the reservoir.
Generation of mechanical oscillation is ubiquitous to wide variety of intracellular processes. We show that catchbonding behaviour of motor proteins provides a generic mechanism of generating spontaneous oscillations in motor-cytoskeletal filament complexes. We obtain the phase diagram to characterize how this novel catch bond mediated mechanism can give rise to bistability and sustained limit cycle oscillations and results in very distinctive stability behaviour, including bistable and non-linearly stabilised in motor-microtubule complexes in biologically relevant regimes. Hitherto, it was thought that the primary functional role of the biological catchbond was to improve surface adhesion of bacteria and cell when subjected to external forces or flow field. Instead our theoretical study shows that the imprint of this catch bond mediated physical mechanism would have ramifications for whole gamut of intracellular processes ranging from oscillations in mitotic spindle oscillations to activity in muscle fibres.
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