Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2020.08.20.228056v1?rss=1 Authors: Govind Kumar, V., Agrawal, S., Suresh Kumar, T. K., Moradi, M. Abstract: Human fibroblast growth factor (FGF) 1 or hFGF1 is a member of the FGF family that isare involved in various vital processes such as cell proliferation, cell differentiation, angiogenesis and wound healing. hFGF1, which is associated with low stability in vivo, is known to be stabilized by binding heparin sulfate, a glycosaminoglycan that aids the protein in the activation of its cell surface receptor. The poor thermal and proteolytic stability of hFGF1 and the stabilizing role of heparin have long been observed experimentally; however, the mechanistic details of these phenomena either phenomenon are still not well understood. Here, we have used a combination of microsecond-level equilibrium molecular dynamics (MD) simulations, and state-of-the-art enhanced sampling MD simulations to quantitatively characterize the structural dynamics of monomeric hFGF1 in the presence and absence of heparin hexasaccharide. We have observed a local conformational changeconformational change in the heparin-binding pocketregion of hFGF1 that only occurs only in the absence of heparin. Several intramolecular hydrogen bonds were also identified within the heparin-binding pocket region, that form only when hFGF1 interacts with heparin. The loss of both intermolecular and intramolecular electrostatic interactions in the absence of heparin plausibly leads to the observed conformational change. This conformational transition results in increased flexibility of the heparin-binding pocket region and provides an explanation for the susceptibility of apo hFGF1 to proteolytic degradation and thermal instability . The hFGF1-heparin interactions) has also been quantified using absolute binding free energy calculations. Binding affinity (Kd) estimates determined computationally using our novel MD approach are in a good quantitative agreement with experimental Kd values from isothermal titration calorimetry experiments. The successful application of a combination of rigorous physics-based simulation techniques microsecond-level MD and accurate free energy calculations and its ability to accurately explain the biomolecular phenomena such as the heparin-mediated stabilization of hFGF1 at a quantitative level, provides open new opportunitiesrepresents a promising approach for studying complex towards understanding biological processesbiomolecular interactions between proteins and their binding partners at a detailed molecular level. using rigorous physics-based simulation techniques. Copy rights belong to original authors. Visit the link for more info