Myosin conformational change


SMD is a novel approach to the study of the dynamics of binding/unbinding events in biomolecular systems and of their elastic properties. The simulations reveal the details of molecular interactions in the course of unbinding, thereby providing important information about binding mechanisms. The advantage of SMD over conventional molecular dynamics is the possibility of inducing relatively large conformational changes in molecules on nanosecond time scales. Other methods, such as umbrella sampling, free energy perturbation (McCammon and Harvey, 1987), and weighted histogram analysis (Kumar ct ah, 1992), aiming at the determination of the energy landscapes, typically involve small conformational changes and require extensive computations to achieve accuracy.  [c.59]

Globular proteins have biological function which they carry out by direct interaction with ligands that may be small atoms or large macromolecules. The protein without the bound ligand is known as the apo form, whereas the bound state is called the holo form. Many proteins are capable of binding more than one ligand, but usually do so on separate domains. The binding sites may be located in the protein interior as in the case of cofactors such as the hemes. Larger ligands most often bind at the surface including in the interdomain region. There is steric and physicochemical complementarity between the interacting surfaces resulting in close packing and favorable polar interactions. The stmcture of a protein domain generally does not alter significantly on binding. An exception is calmodulin, in which a large hinge movement has been observed between its two lobes on binding to a peptide analogue of myosin kinase (12). Sometimes the binding of a ligand at a particular site of a protein can have an effect on the affinity of binding of another ligand at a second site. The related site may be on a different domain of a multidomain protein or a different subunit of an oligomeric protein. This is termed allostery. The allosteric effect can be explained in terms of a conformational change at the primary site inducing a change at the secondary site. Allosteric control is frequendy observed in gene regulation by a feedback mechanism. The binding of a repressor or activator to the DNA sites controlling the synthesis of a protein is modulated by its binding to the synthesized protein itself.  [c.211]

The essence of the sliding filament model is that the myosin head hinds to the actin filament in one position relative to its anchor point on the myosin filament, changes this relative position about 100 A along the fiber axis, and during this process the two filaments slide relative to each other by about the same distance. The myosin head then detaches from the actin filament ready to repeat the process. We will now discuss the molecular mechanisms of the power stroke suggested by Ken Holmes, from the known structures of myosin and the actin-myosin complex, that couple ATP binding and hydrolysis, myosin-actin interactions and the repositioning of the myosin heads by conformational changes.  [c.296]

In the absence of nucleotides, the myosin nucleotide-binding cleft is open, the lever arm is "down," the actin-binding site is intact and this form binds strongly to actin (Figure 14.17a). This is the rigor state into which in the absence of nucleotides the muscle is locked as in rigor mortis. If ATP is added, the myosin head, bound to actin, will bind ATP, and then dissociate from the actin (Figure 14.17b). Binding of ATP to the nucleotide-binding domain in the cleft causes the P loop, which corresponds to the switch II region in G-proteins, described in Chapter 13, to change its conformation. The y-phosphate of ATP plays the same role in this conformational change as the y-phosphate of GTP in G-proteins. This change in the loop conformation is coupled to a major conformational change of parts of the head protein as a result the cleft closes and the region that binds actin releases the actin filament. The bound ATP is then hydrolyzed to ADP and phosphate (Figure 14.17c).  [c.296]

It seems likely, therefore, that as the bound phosphate molecule is released, the cleft starts to open and the myosin head binds to actin (Figure 14.17d). Release of ADP coincides with a conformational change that fully opens the myosin cleft, causing actin to be tightly bound, and moves the lever arm to the "down" position. Since the myosin head is now strongly bound to actin at one end and covalently linked to the myosin fibril at the other  [c.296]

The conformational change of myosin that leads to the sliding of the filaments thus consists of switching a lever arm that changes the relative position of the two ends of the elongated heads hy about 100 A. Part of the energy of ATP hydrolysis must he stored as a mechanical "spring" to drive this conformational change. The two major states described here are not the only states of the actin-myosin complex additional intermediate states are now being defined but it is unlikely that we shall have to change the current overall picture of the mechanism of muscle contraction.  [c.297]

The Coupling Mechanism ATP Hydrolysis Drives Conformation Changes in the Myosin Heads  [c.552]

As shown in the cycle in Figure 17.23a, the myosin heads—with the hydrolysis products ADP and P bound—are mainly dissociated from the actin filaments in resting muscle. When the signal to contract is presented (see following discussion), the myosin heads move out from the thick filaments to bind to actin on the thin filaments (Step 1). Binding to actin stimulates the release of phosphate, and this is followed by the crucial conformational change by the SI myosin heads—the so-called power stroke—and ADP dissociation. In this step (Step 2), the thick filaments move along the thin filaments as the myosin heads relax to a lower energy conformation. In the power stroke, the myosin heads tilt by approximately 45 degrees and the conformational energy of the myosin heads is lowered by about 29 kj/mol. This moves the thick filament approximately 10 nm along the thin filament (Step 3). Subsequent binding (Step 4) and hydrolysis (Step 5) of ATP cause dissociation of the heads from the thin filaments and also cause the myosin heads to shift back to their high-energy conformation with the heads long axis nearly perpendicular to the long axis of the thick filaments. The heads may then begin another cycle by binding to actin filaments. This cycle is repeated at rates up to 5/sec in a typical skeletal muscle contraction. The conformational changes occurring in this cycle are the secret of the energy coupling that allows ATP binding and hydrolysis to drive muscle contraction.  [c.552]

FIGURE 17.23 The mechanism of skeletal muscle contraction. The free energy of ATP hydrolysis drives a conformational change in the myosin head, resulting in net movement of the myosin heads along the actin filament. Inset) A ribbon and space-filling representation of the actin—myosin interaction. (SI myosin image courtesy of Ivan Rayment and Hazel M. Holden, University of Wiseonsin, Madison.)  [c.553]

We know from the discussion above that n-butane has an anti and two gauche forms (mirror images). These are called stable conformers. Molecules having a dihedral angle co (see Fig. 4-18) that is not at a minimum of energy are unstable configurations. Although all three conformers, anti and two gauche forms, are stable in the energetic sense that they are at the minima of potential energy wells, there is enough thermal energy hgT that can be absorbed from the environment at any nomial temperature T 7 0 to drive any conformer up over the potential maximum in Fig. 4-18 and change (twist) it into any other conformer. Interconversion is  [c.125]

Monte Carlo searching becomes more difficult for large molecules. This is because a small change in the middle of the molecule can result in a large displacement of the atoms at the ends of the molecule. One solution to this problem is to hold bond lengths and angles fixed, thus changing conformations only, and to use a small maximum displacement.  [c.182]

In pnnciple ethane has an infinite number of conformations that differ by only tiny increments m their torsion angles Not only is the staggered conformation more stable than the eclipsed it is the most stable of all of the conformations the eclipsed is the least stable Figure 3 4 shows how the potential energy of ethane changes for a 360° rotation about the carbon-carbon bond Three equivalent eclipsed conformations and three equivalent staggered conformations occur during the 360° rotation the eclipsed conformations appear at the highest points on the curve (potential energy maxima) the staggered ones at the lowest (potential energy minima)  [c.107]

In principle ethane has an infinite number of conformations that differ by only tiny increments in their torsion angles. Not only is the staggered conformation more stable than the eclipsed, it is the most stable of all of the conformations the eclipsed is the least stable. Figure 3.4 shows how the potential energy of ethane changes for a 360° rotation about the carbon-carbon bond. Three equivalent eclipsed conformations and three equivalent staggered conformations occur during the 360° rotation the eclipsed conformations appear- at the highest points on the curve (potential energy maxima), the staggered ones at the lowest (potential energy minima).  [c.107]

Stmctural changes can be divided into two general types those of a conformational nature and those involving bond breaking/forming. There are intermediate cases, such as bonds involving metal coordination, but since metal coordination is difficult to model anyway, we will neglect such systems at present. The bottleneck for structural changes is the highest energy point along the reaction path, called the Transition State or Transition Structure (TS) (Chapter 12). Conformational TSs have the same atom types and bonding for both the reactant and product, and can be located on the force field energy surface by standard optimization algorithms. Since confonnational changes are often localized to rotation around a single bond, simply locating the maximum energy structure for rotation (so-called torsional angle driving , see Section 14.5.9) around this bond represents a quite good approximation to the real TS.  [c.47]

Based on our previous experience, we have also studied the effect of selective cross-linking systems on NBR-PVC blends containing dominant PVC phase, 60% by weight. Some experimental results are in Table 10. Evidently, at a higher concentration of BMI the gel content was somewhat higher than for the gel content prorated for NBR content in the blend. It seems a partial crosslinking of PVC or NBR-PVC interface has occurred. The results are in conformity with the mechanical properties of the BMI cured blend. In most of these cases the measured values of mechanical strength has gone through a maximum, indicating a change in the reaction mechanism during the molding process with curatives.  [c.471]

Despite an abundance of modeling methods for ligand-receptor interactions and protein-protein docking (Strynadka et al., 1996) little is known about processes governed by adhesive interactions such as those occuring in the binding and unbinding of ligands. Presently, the prevailing point of view concerning computer simulations describing ligand binding and determining binding affinities is to strive for the ideal of reversibility, as in umbrella sampling and free energy perturbation (McCammon and Harvey, 1987 Ajay and Murcko, 1995 Gilson et al., 1997), with the hope that artifacts induced by the finite rate of conformational changes can be neglected. Reaching this ideal, however, requires extremely slow manipulation and, therefore, prohibitively expensive simulations. This chapter advocates a new computational method,  [c.39]

Figure 14.12 The swinging cross-bridge model of muscle contraction driven by ATP hydrolysis, (a) A myosin cross-bridge (green) binds tightly in a 45 conformation to actin (red), (b) The myosin cross-bridge is released from the actin and undergoes a conformational change to a 90 conformation (c), which then rebinds to actin (d). The myosin cross-bridge then reverts back to its 45° conformation (a), causing the actin and myosin filaments to slide past each other. This whole cycle is then repeated. Figure 14.12 The swinging cross-bridge model of muscle contraction driven by ATP hydrolysis, (a) A myosin cross-bridge (green) binds tightly in a 45 conformation to actin (red), (b) The myosin cross-bridge is released from the actin and undergoes a conformational change to a 90 conformation (c), which then rebinds to actin (d). The myosin cross-bridge then reverts back to its 45° conformation (a), causing the actin and myosin filaments to slide past each other. This whole cycle is then repeated.
Muscle is composed of two sets of interdigitating filaments thick filaments containing the fibrous protein myosin and thin filaments containing F-actin, a helical polymer of the soluble, globular, monomeric G-actin. In addition there are a number of other muscle proteins that regulate muscle activity. When muscles contract, actin filaments and myosin filaments slide with respect to each other. This movement is brought about by rounds of conformational changes of the heads of myosin molecules that project as cross-bridges from the myosin thick filaments to actin subunits in F-actin. Each round requires the hydrolysis of one molecule of ATP. Detailed structural studies of fragments of myosin and of actin at atomic resolution have clarified many of the molecular changes that occur during the movement of myosin cross-bridges.  [c.297]

The only remaining piece of the puzzle is this How does the close coupling of actin-myosin binding and ATP hydrolysis result in the shortening of myofibrils Put another way, how are the model for ATP hydrolysis and the sliding filament model related The answer to this puzzle is shown in Figure 17.23b. The free energy of ATP hydrolysis is translated into a conformation change in the myosin head, so that dissociation of myosin and actin, hydrolysis of ATP, and rebinding of myosin and actin occur with stepwise movement of the myosin SI head along the actin filament. The conformation change in the myosin head is driven by the hydrolysis of ATP.  [c.552]

Fig. 3 shows the evolution of the charge distribution calculated with the PB equation of a set BPTI structures generated from the 200 ps MD simulation in solution. In this simulation the total charge of the protein was set to 5 e, by neutralization of the protein N-terminal group and the use of standard protonation states for all other protonation sites. However, the starting x-ray structure (PDB entry code [12] 4pti) is consistent with fractional ionization of the N-terminal group of 0.6 which indicates that for this structure the probability for this group of being neutral is slightly smaller than that of being charged. It is seen that at the initial stage of simulation (0-100 ps) the maximum net charge was about 5.8 e, in agreement with the fact that the starting structure taken for the simulation favored a larger charge than 5 e. The total charge becomes, however, very rapidly centered at the value of 5 e, so the distribution at 100-200 ps is nearly unimodal around that value, indicating an excellent agreement with the imposed charge during the MD simulation. The result presented in Fig. 3 shows that even a single charge mutation can substantially change the protein conformations explored during the MD simulation. This result not only emphasizes the need for the careful protein charge assigment, but also points out the direction of future development of the MD simulation techniques which would allow for modifying the titration state of a protein during the simulations.  [c.189]

The myosin molecule, which is a dimer consisting of two heavy chains and four light chains, forms a 1400-A-long tail and two heads, each of 120,000 kDa molecular weight (Figure 14.14). The C-terminal regions of the heavy chains are folded into long a helices that form the tail by dimerizing through parallel coiled coils. Fragments of myosin called subfragment 1, or SI, can be cleaved off SI consists of the two light chains and the N-terminal region of one heavy chain that includes the globular head and a short part of the helical tail. The structure of SI from chicken myosin has been determined by the group of Ivan Rayment at the University of Wisconsin, Madison. The fragment is tadpole-like in form, with an elongated head and a tall (Figure 14.15). The head contains a seven-stranded p sheet (green) and numerous associated a helices (red) which form a deep cleft, with the actin-binding site and the nucleotide-binding site on opposite sides of the P sheet. The ATP-binding site contains a typical switch II region, which is also found in the G-proteins (see Chapter 13) that changes conformation depending on whether ATP or ADP is bound. The cleft separates two parts of the head, which are referred to as the 50K upper and 50K lower domains (see Figure 14.15b). The tail, which also provides the connection to the thick filament, has a long extended a helix formed by the heavy chain that binds two light chains (yellow and magenta in Figure 14.15).  [c.294]


See pages that mention the term Myosin conformational change : [c.498]    [c.256]    [c.297]    [c.558]    [c.192]    [c.393]   
Introduction to protein structure (1999) -- [ c.294 , c.296 ]