We've updated our Privacy Policy to make it clearer how we use your personal data.

We use cookies to provide you with a better experience. You can read our Cookie Policy here.

Advertisement
Method To Determine Protein Structure Could Provide Inaccurate Info
News

Poor Drug Design – Could X-Ray Crystallography Be the Culprit?

Method To Determine Protein Structure Could Provide Inaccurate Info
News

Poor Drug Design – Could X-Ray Crystallography Be the Culprit?

Computational model YidC2 protein embedded cell membrane. The modeled loop (yellow), missing in the x-ray crystal structure, is crucial for the stabilization of protein. Credit: Sogol Moradi
Read time:
 

Want a FREE PDF version of This News Story?

Complete the form below and we will email you a PDF version of "Method To Determine Protein Structure Could Provide Inaccurate Info "

First Name*
Last Name*
Email Address*
Country*
Company Type*
Job Function*
Would you like to receive further email communication from Technology Networks?

Technology Networks Ltd. needs the contact information you provide to us to contact you about our products and services. You may unsubscribe from these communications at any time. For information on how to unsubscribe, as well as our privacy practices and commitment to protecting your privacy, check out our Privacy Policy

A new study by chemists at the University of Arkansas shows that X-ray crystallography, the standard method for determining the structure of proteins, can provide inaccurate information about a critical set of proteins - those found in cell membranes - which in turn could be leading to poor and inefficient drug design.

The researchers' findings were published today in Scientific Reports, a Nature publication.

"Two-thirds of all drugs, including those used for chemotherapy, target proteins found on cell membranes," said Mahmoud Moradi, assistant professor of chemistry and biochemstry in the J. William Fulbright College of Arts and Sciences. "Unfortunately, X-ray crystallography, the gold standard for determining the structure of proteins, has many limitations when dealing with those found in the cellular membrane. Our work exposes, and in many ways, explains these limitations."

Considered the workhorse molecules of cells, proteins are responsible for nearly every task in living systems. Some proteins live inside cells, and some reside on the cell's membrane, an outer layer of lipids that separates the cell from its external environment. Membrane proteins are critically important because they regulate the exchange of information and materials between the cell and its environment, a vital task for survival and normal function of the cell because any disorder in protein function can result in disease.

The study of protein function is necessary for understanding the molecular basis of disease. To do this, researchers have relied on X-ray crystallography, the primary tool for determining the shape and structure of proteins. X-ray crystallography is also essential for the purpose of designing drugs that efficiently manipulate the function of proteins. However, the study of membrane protein structure is difficult because their native environment is not compatible with X-ray crystallography. Researchers must remove the proteins from their native environment and place them in an artificial lipid environment before applying the technique.

Moradi and Thomas Harkey - an undergraduate student at the time and now a medical student at the University of Arkansas for Medical Sciences - addressed this problem from a different angle. For roughly two years, they used a supercomputer at the Arkansas High Performance Computing Center to run continuous, microsecond-level computations simulating the molecular dynamics of YidC2, a membrane protein with a crystallographically unresolved cytoplasmic loop in its molecular structure. Cytoplasmic loops are known to have functional significance in membrane proteins.

Moradi and Harkey's simulations demonstrated that YidC2's cytoplasmic loop stabilized the entire protein, particulary the C1 region, a potentially important area for drug design. Highly polar or charged lipid headgroups interacted with and stabilized the loop. This finding demonstrated that unresolved loops of membrane proteins could be important for the stabilization of proteins, despite the apparent lack of molecular structure.

"Typically, if part of a protein is not resolved in X-ray crystallography, it is interpreted as lacking a particular structure," Moradi said. "We show that for membrane proteins and particularly parts of the protein that interact with the cell membrane, this interpretation is not accurate and could be misleading. We think that the alternative explanation for the disorder could be that the protein is not studied in its native membrane environment."

Moradi said their results also demonstrated that computational chemistry and supercomputing technology can be used to model membrane proteins more accurately in an environment that mimics their physiological environment.

Reference: Harkey, et al. (2019) The Role of a Crystallographically Unresolved Cytoplasmic Loop in Stabilizing the Bacterial Membrane Insertase YidC2. Scientific Reports. DOI: https://doi.org/10.1038/s41598-019-51052-9 

This article has been republished from the following materials. Note: material may have been edited for length and content. For further information, please contact the cited source.

Advertisement