RESEARCH: MYOSINS
FOLDING PROJECT #12299 PROFILE

This project studies blebbistatin, a drug that blocks muscle protein (myosin) function. Researchers are using computer simulations to see how blebbistatin affects myosin's shape and ability to move. Understanding this could lead to better treatments for heart diseases caused by faulty myosin.

Note: This TLDR is a simplication and may not be 100% accurate.

These projects are attempts to better understand the behavior of a longstanding drug lead, blebbistatin, and its effects on the motor domain of skeletal muscle myosin.

Myosins are ubiquitous and their motor domains are highly conserved, so while drugging them has potential especially in the context of certain muscle related diseases like hypertrophic cardiomyopathy (a relatively prevalent form of genetic heart disease), understanding how a potential drug interacts with myosin isoforms from first principles will help seed development efforts to avoid side effects. Myosin works by cycling through an ATP hydrolysis (ATP--Adenosine Tri-Phosphate--is the energy currency of the cell, and cutting the third phosphate off hydrolitically is how that currency is spent) driven process where it binds actin, undergoes a conformational (a particular arrangement of the atoms in the protien) change, and then releases actin (allowing collections of myosins to work in concert to pull along the length of an actin fiber).

A common mode of action for inhibitors of myosin is that they will get a motor domain stuck in a particular step in the cycle.

Blebbistatin is an inhibitor that binds to a subclass of myosin at a cryptic site and inhibits phosphate release, which is a necessary step in the cycle. To understand how blebbistatin impacts the conformations the protein can access, we've started simulaitons from four different chemical compositions:

• 12296: Blebbistatin only.

  All other binding sites are vacant.

  Experimentally, blebbistatin is believed to not bind this state.

  We hope to see what impact it may have on the ATP/ADP+Phosphate binding site.

• 12297: ADP, Phosphate, and Blebbistatin.

  This is thought to be the mode of action of blebbistatin.

  It causes the Phosphate present in this conformation to be held more tightly, thus preventing the enzyme from cycling.

• 12298: ADP and Blebbistatin.

  This simulation will allow us to ask what is different about the phosphate binding site when Blebbistatin is present, to see if it maintains conformations that would bind phosphate well even when it is no longer present.

• 12299: ADP only.

  To see how the blebbistatin binding site fluctuates when the phosphate is not present.

  Because blebbistatin is supposed to be selective for the states that are compatible with phosphate binding, this will help us elucidate the coupling between the two sites.

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blebbistatin

A drug that inhibits myosin.

Blebbistatin is a compound that acts as an inhibitor of myosin, a protein involved in muscle contraction. It is being studied for its potential therapeutic effects on muscle-related diseases.

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myosin

A motor protein responsible for muscle contraction.

Myosin is a crucial protein found in muscles that powers the process of contraction. It interacts with another protein called actin to generate force and movement.

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ATP

Adenosine Tri-Phosphate

ATP is the primary energy currency of cells. It provides the energy needed for various cellular processes, including muscle contraction.

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ADP

Adenosine Di-Phosphate

ADP is a molecule formed when ATP loses one phosphate group. It plays a role in energy transfer within cells.

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actin

A protein that interacts with myosin to facilitate muscle contraction.

Actin is a protein that forms thin filaments in muscles. It works together with myosin to produce the sliding filament mechanism of muscle contraction.

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hypertrophic cardiomyopathy

A genetic heart disease characterized by thickening of the heart muscle.

Hypertrophic cardiomyopathy is a condition where the heart muscle becomes abnormally thick, making it harder for the heart to pump blood effectively. It is often caused by genetic mutations.