In-Silico Studies on Fibrinogen Domain Adsorption on Polylactic Acid

*All authors contributed equally<br/><br/>Fibrinogen, a vital blood clotting protein, transforms into active fibrin via thrombin activation, creating a scaffold for clots. It is key in interactions with medical device materials, especially those prone to adverse clotting. Investigating material-blood protein interactions, like those with polylactic acid (PLA), which is used for its biocompatibility, can aid in preventing device-induced clots and enhancing safety.<br/>Prior research demonstrates the impact of surface chemistry on adsorbed fibrinogen's conformation, orientation, fiber formation, and platelet adhesion. This is attributed to distinct surface properties of fibrinogen domains: D and central E (C_e) domains are hydrophobic, while the αC domain is hydrophilic. On hydrophobic surfaces like PLA, D and C_e domains strongly adhere (with C_e showing weaker adherence) while the αC domain remains detached, promoting lateral aggregation via αC domain linkage. Conversely, on hydrophilic surfaces, αC domains bind to the C_e domain, reducing lateral aggregation. Additionally, P12, a proven stent coating, reduces fibrinogen fiber count on hydrophobic surfaces and supports endothelial cell growth without adverse effects. P12 obstructs the D domain's hole, impeding fiber formation; it potentially affects αC domains by surface binding as well.<br/>To study this critical interaction between P12 and fibrinogen, we conducted molecular dynamics simulations. In order to lessen the computational cost, the problem was divided into parts for the three fibrinogen domains. For the D and C_e domains, the simulations were identical: run each domain alone in water, each domain face down on PLA, and each domain face up on PLA. By accounting for the different orientations of the domains on PLA, the actual binding configuration for each domain could be deduced as it is currently unknown. For the central complex (αC and C_e domain), umbrella sampling and steered molecular dynamics (SMD) were done to gain insight into the free energy landscape of the complex when the αC domains are separated and to determine the force necessary to pull the αC domain segments apart.<br/>After 4.45 ns of D domain simulation, the total energy of the system was -2.99795e+06. After 6.01 ns of C_e domain simulation, the total energy of the system was -1.38023e+06. Both domains of the fibrinogen protein were shown to have stably folded, with reasonably invariant radii of gyration. Our next steps include running simulations with the D and C_e domains face down and face up on PLA, to examine the lowest energy conformations and chemical behaviors of these surface interactions. Moreover, we will use data from the SMD and umbrella sampling to train a machine learning model to predict whether the αC domain segments will be pulled apart, given various factors such as thermodynamics values and relative orientation.