A molecular dynamics study of the FGF1/FGF2 heterodimer in human fibroblasts.

Abstract

A family of mitogenic proteins known as fibroblast growth factors is responsible for regulating cell division and growth throughout the body. These signaling molecules are also crucial for wound healing, repairing, and regenerating damaged tissue quickly in order to prevent chronic injuries. Phylogeny and sequence homology classify them into seven subfamilies 1, 4, 7, 8, 9, 11, and 15. Out of all the FGF members, the FGF1 subfamily, consisting of FGF1 and FGF2, is the most prominent and well-studied. It is believed that FGF1 plays the most significant role in cell proliferation, whereas FGF2 plays a vital role in the angiogenic activity. The half-life of FGF1 and FGF2 is significantly shortened under physiological conditions due to their low thermal and proteolytic stability. Heparin is one of the FGF ligands that induce conformational changes in these molecules, which are needed for the FGFs to interact with the receptors (FGFR1, FGFR2, FGFR3, and FGFR4) and initiate the signaling cascade. Besides the limitations associated with individual FGF1 and FGF2, another disadvantage is that FGF1 binds universally to all FGFR1-4, whereas FGF2 binds only to FGFR2. It may be possible that an FGF1-FGF2 dimer facilitates the binding between FGF2 and FGFR2, allowing FGF1 to bind to any adjacent receptor, thereby activating both FGF1 and FGF2 to promote cell growth and angiogenesis. In this study, I have modeled an FGF1-FGF2 fused protein and used microsecond-level molecular dynamics simulations to study the differential behavior of several engineered protein variants regardless of heparin exposure to achieve high thermal stability and enhanced biological functions. Consequently, I have observed an increase in the stability of each monomer within the dimer protein.