Scientists know that a better understanding of how proteins bond could lead to more effective treatments for genetic disorders and other life-threatening conditions.
Now, a pair of Florida State University researchers' new theory has been proven to accurately predict the association rate for proteins. Their theory is outlined in the February issue of the scientific journal Structure.
"A protein can have multiple targets or can be targeted by multiple molecules," said Professor Huan-Xiang Zhou, who serves on the faculty of FSU's School of Computational Science and department of physics. "Rapid association between proteins is crucial in a wide array of biological processes, such as the utilization of and defense against toxins; the activation of receptor proteins on cell membranes by growth hormones; and the regulation of actin polymerization, which influences the physical structure of living cells. The association rate thus plays a critical role in the overall health of the organism."
Mutations are one factor that can disrupt quick association between proteins and lead to disease, he said.
"For example, Wiskott-Aldrich syndrome, a pediatric genetic disorder characterized by eczema, immune deficiencies and low blood-platelet counts, can be traced to mutations on the Wiskott-Aldrich syndrome protein," Zhou said. "Normally, fast association of the protein with other biomolecules is critical for the creation of proper cell structures. The failure of the protein to associate quickly, then, is the root cause of the condition."
In their Structure paper, Zhou and graduate student Razmi Alsallaq put forth a new theory that has been proven to accurately predict the association rate for proteins by developing a theoretical model for the association process. A central component of the model is the transition state, a phase that two associating proteins go through before finally becoming a specific complex. The rate prediction is broken into two parts: how much the rate would be if the proteins find each other purely through random motion, and how much electrical attraction increases the rate.
"This theory opens numerous opportunities for further study," Zhou said. "For example, we now can begin to uncover the molecular bases of large variations in association rate among proteins. It also might be possible to design proteins with the desired association rate."
Attila Szabo, chief of the Theoretical Biophysical Chemistry section of the National Institutes of Health, described the Structure paper as "the most comprehensive investigation yet conducted of protein-protein association rate. It provides convincing evidence that the remarkable simplification of the calculation of association rates between proteins, proposed by Zhou and coworkers, really works."
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