Understanding Folding of bFGF and Potential Cellular Protective Mechanisms of Neural Cells

Abstract

Traumatic brain injury (TBI) is a serious health condition that affects an increasing number of people, especially veterans and athletes. TBI causes serious consequences because of its long-lasting impact on the brain and its alarming frequency of occurrence. Although the brain has some natural protective mechanisms, the processes that trigger them are poorly understood. Fibroblast growth factor (FGF) proteins interact with receptor proteins to protect cells. Gaps in the literature include how basic-FGF (bFGF) is activated by heparin, can heparin-like molecules induce neural protection, and the effect of allosteric binding on bFGF activity. To fill the gap in our understanding, we applied temperature replica exchange to study the influence of heparin binding to bFGF and how mutations in bFGF influence stability. A new favorable binding site was identified by comparing free energies computed from the potential of mean force (PMF). Although the varied sugars studied resulted in different interactions with bFGF compared to heparin, they each produced structural effects similar to those of bFGF that likely facilitate receptor binding and signaling. Our results also demonstrate how point mutations can trigger the same conformational change that is believed to promote favorable interactions with the receptor. A deeper atomic-level understanding of how chemicals are released during TBI is needed to improve the development of new treatments for TBI and could contribute to a better understanding of other diseases.