AVS 50th International Symposium
    Biomaterial Interfaces Wednesday Sessions
       Session BI-WeM

Paper BI-WeM5
Molecular Modeling of Adsorption-Induced Exposure of Integrin Binding Sites in Fibrinogen

Wednesday, November 5, 2003, 9:40 am, Room 317

Session: Bionanoscale Analysis: Theory to Experiment
Presenter: M.A. Agashe, Clemson University
Authors: M.A. Agashe, Clemson University
S.J. Stuart, Clemson University
L. Tang, The University of Texas at Arlington
R.A. Latour, Clemson University
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Implants invoke inflammatory responses from the body even if they are chemically inert and non-toxic. It has been shown that a crucial precedent event in the inflammatory process is the spontaneous adsorption of fibrinogen on implant surfaces, which is typically followed by the presence of phagocytic cells. It has been found that interactions between the phagocyte integrin Mac-1 and one short sequence within the fibrinogen D domain (@gamma@190 to 202) partially explain phagocyte accumulation at implant surfaces. However, it is still unknown what makes adsorbed fibrinogen proinflammatory when soluble fibrinogen is not. One premise is that adsorption exposes the normally occult P1(@gamma@190 to 202) and P2 (@gamma@377 to 395) epitopes that reside in the D domains of fibrinogen; these epitopes are also involved in thrombin-mediated conversion of fibrinogen to fibrin. The objective of our research is to use molecular modeling to investigate how surface chemistry influences the adsorption behavior of the D fragment of fibrinogen with a particular focus on characterizing adsorption-induced conformational changes in the P1 and P2 region of this fibrinogen fragment that may lead to epitope exposure for integrin binding. Modeling is being conducted using Insight II software (Accelrys) with the CHARMM force field. The adsorption of the @gamma@ chain of fibrinogen is being simulated on 4 types of SAM surfaces (hydrophobic, hydrophilic, + & - charged). An implicit solvent model (generalized Born) is being used to represent the solvent and solvent-mediated interactions during the molecular dynamics simulations. The study of these changes in conformation will help us to understand the likely molecular mechanisms that are responsible for the exposure of the P1 and P2 domains, and how this may be able to be controlled by surface chemistry. This understanding may help in the design of biomaterial surfaces with improved biocompatibility.