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Initial conformation of kinesin's neck linker  [PDF]
Yi-Zhao Geng,Qing Ji,Shu-Xia Liu,Shiwei Yan
Quantitative Biology , 2013, DOI: 10.1088/1674-1056/23/10/108701
Abstract: How ATP binding initiates the docking process of kinesin's neck linker is a key question in understanding kinesin mechanism. It is believed that the formation of an extra turn structure by the first three amino acids of neck linker (LYS325, THR326, ILE327 in 2KIN) is crucial for initiating the docking process. But the initial conformation of neck linker (specially the three amino acids of the extra turn) and the neck linker docking initiation mechanism remain unclear. By using molecular dynamics method, we investigate the initial conformation of kinesin's neck linker in the docking process. We find that, in the initial state of NL docking process, NL still has interactions with {\beta}0 and forms a conformation similar to the "cover-neck bundle" structure proposed by Hwang et al. [Structure 2008, 16(1): 62-71]. From this initial structure, the docking of the "cover-neck bundle" structure can be achieved. The motor head provides a forward force on the initial cover-neck bundle structure through ATP-induced rotation. This force, together with the hydrophobic interaction of ILE327 with the hydrophobic pocket on the motor head, drives the formation of the extra turn and initiates the neck linker docking process.
Electrostatically Biased Binding of Kinesin to Microtubules  [PDF]
Barry J. Grant,Dana M. Gheorghe,Wenjun Zheng,Maria Alonso,Gary Huber,Maciej Dlugosz,J. Andrew McCammon,Robert A. Cross
PLOS Biology , 2012, DOI: 10.1371/journal.pbio.1001207
Abstract: The minimum motor domain of kinesin-1 is a single head. Recent evidence suggests that such minimal motor domains generate force by a biased binding mechanism, in which they preferentially select binding sites on the microtubule that lie ahead in the progress direction of the motor. A specific molecular mechanism for biased binding has, however, so far been lacking. Here we use atomistic Brownian dynamics simulations combined with experimental mutagenesis to show that incoming kinesin heads undergo electrostatically guided diffusion-to-capture by microtubules, and that this produces directionally biased binding. Kinesin-1 heads are initially rotated by the electrostatic field so that their tubulin-binding sites face inwards, and then steered towards a plus-endwards binding site. In tethered kinesin dimers, this bias is amplified. A 3-residue sequence (RAK) in kinesin helix alpha-6 is predicted to be important for electrostatic guidance. Real-world mutagenesis of this sequence powerfully influences kinesin-driven microtubule sliding, with one mutant producing a 5-fold acceleration over wild type. We conclude that electrostatic interactions play an important role in the kinesin stepping mechanism, by biasing the diffusional association of kinesin with microtubules.
Electrostatically Biased Binding of Kinesin to Microtubules  [PDF]
Barry J. Grant equal contributor,Dana M. Gheorghe equal contributor,Wenjun Zheng,Maria Alonso,Gary Huber,Maciej Dlugosz,J. Andrew McCammon ? ,Robert A. Cross ?
PLOS Biology , 2011, DOI: 10.1371/journal.pbio.1001207
Abstract: The minimum motor domain of kinesin-1 is a single head. Recent evidence suggests that such minimal motor domains generate force by a biased binding mechanism, in which they preferentially select binding sites on the microtubule that lie ahead in the progress direction of the motor. A specific molecular mechanism for biased binding has, however, so far been lacking. Here we use atomistic Brownian dynamics simulations combined with experimental mutagenesis to show that incoming kinesin heads undergo electrostatically guided diffusion-to-capture by microtubules, and that this produces directionally biased binding. Kinesin-1 heads are initially rotated by the electrostatic field so that their tubulin-binding sites face inwards, and then steered towards a plus-endwards binding site. In tethered kinesin dimers, this bias is amplified. A 3-residue sequence (RAK) in kinesin helix alpha-6 is predicted to be important for electrostatic guidance. Real-world mutagenesis of this sequence powerfully influences kinesin-driven microtubule sliding, with one mutant producing a 5-fold acceleration over wild type. We conclude that electrostatic interactions play an important role in the kinesin stepping mechanism, by biasing the diffusional association of kinesin with microtubules.
A Brownian Dynamics Model of Kinesin in Three Dimensions Incorporating the Force-Extension Profile of the Coiled-Coil Cargo Tether  [PDF]
P. J. Atzberger,C. S. Peskin
Quantitative Biology , 2009, DOI: 10.1007/s11538-005-9003-6
Abstract: The Kinesin family of motor proteins are involved in a variety of cellular processes that transport materials and generate force. With recent advances in experimental techniques, such as optical tweezers which can probe individual molecules, there has been an increasing interest in understanding the mechanisms by which motor proteins convert chemical energy into mechanical work. Here we present a mathematical model for the chemistry and three dimensional mechanics of the Kinesin motor protein which captures many of the force dependent features of the motor. For the elasticity of the tether that attaches cargo to the motor we develop a method for deriving the non-linear force-extension relationship from optical trap data. For the Kinesin heads, cargo, and microscope stage we formulate a three dimensional Brownian Dynamics model that takes into account excluded volume interactions. To efficiently compute statistics from the model an algorithm is proposed that uses a two step protocol that separates the simulation of the mechanical features of the model from the chemical kinetics of the model. Using this approach for a bead transported by the motor, the force dependent average velocity and randomness parameter are computed and compared with the experimental data.
The Force Exerted by a Molecular Motor  [PDF]
Michael E. Fisher,Anatoly B. Kolomeisky
Physics , 1999, DOI: 10.1073/pnas.96.12.6597
Abstract: The stochastic driving force exerted by a single molecular motor (e.g., a kinesin, or myosin) moving on a periodic molecular track (microtubule, actin filament, etc.) is discussed from a general viewpoint open to experimental test. An elementary "barometric" relation for the driving force is introduced that (i) applies to a range of kinetic and stochastic models, (ii) is consistent with more elaborate expressions entailing explicit representations of externally applied loads and, (iii) sufficiently close to thermal equilibrium, satisfies an Einstein-type relation in terms of the velocity and diffusion coefficient of the (load-free) motor. Even in the simplest two-state models, the velocity-vs.-load plots exhibit a variety of contrasting shapes (including nonmonotonic behavior). Previously suggested bounds on the driving force are shown to be inapplicable in general by analyzing discrete jump models with waiting time distributions.
Mechanical control of the directional stepping dynamics of the kinesin motor  [PDF]
Changbong Hyeon,José N. Onuchic
Quantitative Biology , 2007, DOI: 10.1073/pnas.0708828104
Abstract: Among the multiple steps constituting the kinesin's mechanochemical cycle, one of the most interesting events is observed when kinesins move an 8-nm step from one microtubule (MT)-binding site to another. The stepping motion that occurs within a relatively short time scale (~100 microsec) is, however, beyond the resolution of current experiments, therefore a basic understanding to the real-time dynamics within the 8-nm step is still lacking. For instance, the rate of power stroke (or conformational change), that leads to the undocked-to-docked transition of neck-linker, is not known, and the existence of a substep during the 8-nm step still remains a controversial issue in the kinesin community. By using explicit structures of the kinesin dimer and the MT consisting of 13 protofilaments (PFs), we study the stepping dynamics with varying rates of power stroke (kp). We estimate that 1/kp <~ 20 microsec to avoid a substep in an averaged time trace. For a slow power stroke with 1/kp>20 microsec, the averaged time trace shows a substep that implies the existence of a transient intermediate, which is reminiscent of a recent single molecule experiment at high resolution. We identify the intermediate as a conformation in which the tethered head is trapped in the sideway binding site of the neighboring PF. We also find a partial unfolding (cracking) of the binding motifs occurring at the transition state ensemble along the pathways prior to binding between the kinesin and MT.
Mapping the Structural and Dynamical Features of Kinesin Motor Domains  [PDF]
Guido Scarabelli,Barry J. Grant
PLOS Computational Biology , 2013, DOI: 10.1371/journal.pcbi.1003329
Abstract: Kinesin motor proteins drive intracellular transport by coupling ATP hydrolysis to conformational changes that mediate directed movement along microtubules. Characterizing these distinct conformations and their interconversion mechanism is essential to determining an atomic-level model of kinesin action. Here we report a comprehensive principal component analysis of 114 experimental structures along with the results of conventional and accelerated molecular dynamics simulations that together map the structural dynamics of the kinesin motor domain. All experimental structures were found to reside in one of three distinct conformational clusters (ATP-like, ADP-like and Eg5 inhibitor-bound). These groups differ in the orientation of key functional elements, most notably the microtubule binding α4–α5, loop8 subdomain and α2b-β4-β6-β7 motor domain tip. Group membership was found not to correlate with the nature of the bound nucleotide in a given structure. However, groupings were coincident with distinct neck-linker orientations. Accelerated molecular dynamics simulations of ATP, ADP and nucleotide free Eg5 indicate that all three nucleotide states could sample the major crystallographically observed conformations. Differences in the dynamic coupling of distal sites were also evident. In multiple ATP bound simulations, the neck-linker, loop8 and the α4–α5 subdomain display correlated motions that are absent in ADP bound simulations. Further dissection of these couplings provides evidence for a network of dynamic communication between the active site, microtubule-binding interface and neck-linker via loop7 and loop13. Additional simulations indicate that the mutations G325A and G326A in loop13 reduce the flexibility of these regions and disrupt their couplings. Our combined results indicate that the reported ATP and ADP-like conformations of kinesin are intrinsically accessible regardless of nucleotide state and support a model where neck-linker docking leads to a tighter coupling of the microtubule and nucleotide binding regions. Furthermore, simulations highlight sites critical for large-scale conformational changes and the allosteric coupling between distal functional sites.
Analysis of kinesin mechanochemistry via simulated annealing  [PDF]
B. D. Jacobson,L. J. Herskowitz,S. J. Koch,S. R. Atlas
Quantitative Biology , 2014,
Abstract: The molecular motor protein kinesin plays a key role in fundamental cellular processes such as intracellular transport, mitotic spindle formation, and cytokinesis, with important implications for neurodegenerative and cancer disease pathways. Recently, kinesin has been studied as a paradigm for the tailored design of nano-bio sensor and other nanoscale systems. As it processes along a microtubule within the cell, kinesin undergoes a cycle of chemical state and physical conformation transitions that enable it to take ~100 regular 8.2-nm steps before ending its processive walk. Despite an extensive body of experimental and theoretical work, a unified microscopic model of kinesin mechanochemistry does not yet exist. Here we present a methodology that optimizes a kinetic model for kinesin constructed with a minimum of a priori assumptions about the underlying processive mechanism. Kinetic models are preferred for numerical calculations since information about the kinesin stepping mechanism at all levels, from the atomic to the microscopic scale, is fully contained within the particular states of the cycle: how states transition, and the rate constants associated with each transition. We combine Markov chain calculations and simulated annealing optimization to determine the rate constants that best fit experimental data on kinesin speed and processivity.
The relevance of neck linker docking in the motility of kinesin  [PDF]
Andras Czovek,Gergely J. Szollosi,Imre Derenyi
Physics , 2008, DOI: 10.1016/j.biosystems.2008.04.006
Abstract: Conventional kinesin is a motor protein, which is able to walk along a microtubule processively. The exact mechanism of the stepping motion and force generation of kinesin is still far from clear. In this paper we argue that neck linker docking is a crucial element of this mechanism, without which the experimentally observed dwell times of the steps could not be explained under a wide range of loading forces. We also show that the experimental data impose very strict constraints on the lengths of both the neck linker and its docking section, which are compatible with the known structure of kinesin.
A structural perspective on the dynamics of kinesin motors  [PDF]
Changbong Hyeon,José N. Onuchic
Physics , 2011, DOI: 10.1016/j.bpj.2011.10.037
Abstract: Despite significant fluctuation under thermal noise, biological machines in cells perform their tasks with exquisite precision. Using molecular simulation of a coarse-grained model and theoretical arguments we envisaged how kinesin, a prototype of biological machines, generates force and regulates its dynamics to sustain persistent motor action. A structure based model, which can be versatile in adapting its structure to external stresses while maintaining its native fold, was employed to account for several features of kinesin dynamics along the biochemical cycle. This analysis complements our current understandings of kinesin dynamics and connections to experiments. We propose a thermodynamic cycle for kinesin that emphasizes the mechanical and regulatory role of the neck-linker and clarify issues related the motor directionality, and the difference between the external stalling force and the internal tension responsible for the head-head coordination. The comparison between the thermodynamic cycle of kinesin and macroscopic heat engines highlights the importance of structural change as the source of work production in biomolecular machines.
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