Conformational changes, diffusion and collective behavior in monomeric kinesin-based motility

Abstract

Molecular motors convert chemical energy into mechanical motion and power the transport of material within living cells; the motion of a motor is thought to be influenced by stochastic chemical state transitions of the molecule as well as intramolecular diffusion of one motor head seeking the next binding site. Existing models for the motility of single-headed monomeric motors that map the system to a simplified two-state Brownian ratchet have some predictive power, but in general are unable to elucidate the contributions of different molecular level processes to the overall effective parameters. In this work, we build a detailed molecular level model of monomeric kinesin motility that naturally incorporates conformational changes (power strokes) and biased diffusion. Our results predict that mean velocity is most sensitive to the power stroke size, while run length distribution is sensitive primarily to the strength of the microtubule bias potential with a weak dependence on power stroke that can be tuned by the strength of an applied load. In addition, we demonstrate that motor pairs attached to the same cargo can cooperatively function to increase motility in both the plus- and minus-end directions. These findings illustrate the importance of a detailed mechanochemical model for dissecting the contributions of microscopic parameters to monomeric kinesin dynamics.

Cargo surface fluidity can reduce inter-motor mechanical interference, promote load-sharing and enhance processivity in teams of molecular motors

“…Defects in motor function can impair normal cell functioning and lead to a variety of pathologies including neurodegenerative diseases like Alzheimer’s disease and ALS [ 4 – 9 ]. Given its importance in vivo , there has been a lot of work done over the years in understanding motor function in the transport context ranging from single molecule studies that elucidate the detailed mechanistic workings of motors [ 10 – 17 ] to the functioning of multiple motors and their co-ordination [ 18 – 27 ]. Several theoretical and in vitro experimental studies [ 28 – 32 ] indicate that the collective behavior of motors is critically influenced by their coupling to each other resulting in observable effects in transport speeds and run lengths.…”

Cooperative protofilament switching emerges from inter-motor interference in multiple-motor transport

“…In this SA state, motors diffuse along the microtubule binding lattice, resulting in the rapid and discrete displacement perpendicular to the microtubule of cargos transported by multiple motors. The existence of a SA state has been suggested previously [27][28][29][30] to act as a tether influencing the on/off rates of an individual motor dimer. In our study, since we find that DTDs geometrically require only the shifting of a single motor head, as opposed to the entire functional dimer, to an adjacent protofilament (Supplement Discussion 1), we expli-citly allow individual motor heads within each dimer to make contact across different protofilaments in the weakly associated SA state.…”

Cargo-mediated mechanisms reduce inter-motor mechanical interference, promote load-sharing and enhance processivity in teams of molecular motors

“…Defects in motor function can impair normal cell functioning and lead to a variety of pathologies including neurodegenerative diseases like Alzheimer's disease and ALS [4][5][6][7][8][9]. Given its importance in vivo, there has been a lot of work done over the years in understanding motor function in the transport context ranging from single molecule studies that elucidate the detailed mechanistic workings of motors [10][11][12][13][14][15][16][17] to the functioning of multiple motors and their co-ordination [18][19][20][21][22][23][24][25][26][27]. Several theoretical and in vitro experimental studies [28][29][30][31][32] indicate that the collective behavior of motors is critically influenced by their coupling to each other resulting in observable effects in transport speeds and run lengths.…”