Myosin II motor

Kovacs, M., Malnasi-Csizmadia, A., Woolley, R. J., and Bagshaw, R. J. (2002). Analysis of nucleotide binding to Dictyostelium myosin II motor domains containing a single tryptophan near the active site./. Biol. Chem. 277, 28459-28467. 

The structure of the myosin-II motor domain has been determined in various nucleotide states by crystal structure analysis using constructs originating from diverse sources (chicken skeletal and smooth muscle... 

Figure 1.5. The waters of Thales of the myosin II motor. Stereo views of the crystal structure of the myosin motor domain of Dictostelium discoidium in presence of ATP are shown. A Space-filling display showing water molecules on a sculptured surface of the myosin II motor. B Those water molecules throughout the entire structure that are sufficiently fixed in space to be seen by X-ray diffraction are...

In Chapter 8, more structural background and molecular details of contraction exhibited by the linear myosin II motor are considered after, in Chapter 5, the physical basis for the apolar (oil-like)-polar (vinegar-like) repulsive energy that controls hydrophobic association is experimentally and analytically developed. The crystal structures of the cross-bridge of scallop muscle provide remarkable examples of the consilient mechanism functioning in this protein-based machine ... 

The relationship between the states of the myosin II motor domain, subfragment 1 (SI), and waters of hydrophobic hydration has been directly observed by the same microwave dielectric relaxation measurements as used with the data in Figures 5.24 and 5.25. Suzuki and coworkers have observed the ADP-bound state of SI to have more water of hydrophobic hydration than the ADP Pj state, that is, than the most polar state. Thus, the effects of the additional negative charges are to destroy water of hydrophobic hydration and to raise the value of T, above physiological temperatures. The removal of the phosphate would result in an increase in A and a lowering of T, below the physiological temperature with the consequence of the association of paired... 

In our view, AG.p provides the basis whereby raising the free energy of ADP and P , by forced apposition of the very hydrophobic side of the y-rotor in ATP synthase, results in synthesis of ATP. Also, in myosin II motor AG,p provides the basis whereby this ATPase drives muscle contraction. In particular, in broad-brush strokes, ATP binds in a cleft directed in two directions, (1) toward the hydrophobic association of the cross-bridge to actin binding site and (2) toward the hydrophobic association between the head of the lever arm and the amino-terminal domain of the cross-bridge. Directing the ATP thirst for water in both... 

The consilient mechanism depicted in the elementary structures of Figure 8.2 are relevant to protein function arising out of association of globular components of molecular machines. The principles arise in almost textbook fashion in the function of the myosin II motor where the key charged species are ATP, ADP, and P, but in an important way also include the charged side chains (see section 8.5.3). 

In terms of the molecular process whereby ATP forms and functions as biology s energy coin, there are two aspects—the protonation/ deprotonation of carboxylates due to a proton concentration gradient that drives a rotor to form ATP from ADP and Pi, as in the ATP synthase, and the molecular process whereby the breakdown of ATP to ADP with release of Pj drives the protein-based machines of biology, as in the myosin II motor of muscle contraction. 

The multivalent phosphates, already significantly limited in hydration, can be expected to reach out substantially further than carboxylates in their search for adequate hydration. This effect becomes enhanced when phosphate access to water is limited. When the phosphate occurs at the base of a cleft, the direction for access of water becomes severely limited and the thirst for hydration can be directed by the cleft to target sites of hydrophobic association. In other words, the cleft functions as a conduit to direct the thirst for hydration. By means of the cleft, the capacity for disrupting hydrophobic hydration to target sites can be boosted by effecting separation of ion pairs enroute, which boost the polar species capacity to disrupt hydrophobic hydration. Accordingly, the use of structure to direct the forces of apolar-polar repulsion becomes a useful design feature in certain ATP-driven protein-based machines, such as the myosin II motor. 

In particular, as a step in the functional cycle of the myosin II motor, ATP binding occurs at a water-filled cleft." In the scallop muscle, as shown below, the water-filled cleft can be seen to communicate in two directions. In one direction it communicates with the hydrophobic... 

By the hydrophobic consilient mechanism for the myosin II motor and specifically by means of AG p, ATP binding effects both hydrophobic dissociation from the actin binding site and release of the hydrophobic association at the head of the lever arm, allowing the cross-bridge to move forward toward the next attachment site. Of course, loss of phosphate would reconstitute the hydrophobic associations, that is, would effect hydrophobic re-attachment to the actin binding site in concert with re-association of the head of the lever arm with the amino-termincil domain to result in the powerstroke. Section 8.5.4 presents crystal structure stereo views from which the above-noted perspective derives. 

Contraction by the muscle myosin II motor is another example of hydrophobic association... 

The Myosin II Motor of Muscle Contraction, a Representative ATPase... 

Whether at the anatomical level with the phenomenon of rigor or at the myofibril level with the variables of physiology, an extensive coherence of phenomena exists. Now we address the myosin II motor at the molecular level to deter-... 

In the context of relevance of the consilient mechanism to function of the myosin II motor, remarkable points are the location and orientation of ATP molecules bound to the crossbridge and access to control hydrophobic associations/dissociations. As considered below in section S.5.4.2, narrow clefts function as conduit through which forces arising from the polar phosphates are directed at a target site. 

In this section on the myosin II motor, coherence of phenomena with that of the consilient mechanisms of energy conversion is addressed at the molecular level. Specifically, the importance of hydrophobic interactions is noted, as has been generally appreciated. More to the point, the presence of the apolar-polar repulsive free energy of hydration appears as a prominent factor in the contraction/relaxation cycle, and this has not been previously appreciated. 

Crystal Structure Analyses and Consilient Mechanisms in the Myosin II Motor... 

Hydrolysis of ATP to release the y-phosphate as Pi that leaves the structure, therefore, has two consequences. Strong hydrophobic association is re-established between the cross-bridge and the actin binding site, and strong hydro-phobic association is re-established between the amino-terminal domain and the head of the lever arm to provide the powerstroke. This perspective resides at the heart of the proposed contribution of the hydrophobic consilient mechanism to function of the myosin II motor. It is considered further below and most directly in section 8.S.4.7. 

The above perspectives are natural consequences of both the hydrophobic and the elastic consilient mechanisms as applied to the structural data on the myosin II motor. Here we briefly explore the elastic element. An ideal elastomer exhibits exactly reversible stress-strain curves with complete recovery on relaxation of the energy of deformation. On the other hand, an elastomer that exhibits hysteresis does not recover all of the energy on relaxation that was expended on deformation. Accordingly, efficient muscle contraction should involve the deformation of near-ideal elastic segments to utilize more efficiently the energy expended in driving contraction. The mechanism of elasticity that can provide such near-ideal elasticity is the damping of internal chain dynamics on extension. 

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