Human blood coagulation factor XI (FXI) is a serine protease that participates in the early phase of the intrinsic pathway of blood coagulation. It circulates in blood as an inactive homodimeric glycoprotein composed of two subunits of 607 amino acids, each containing four 90- or 91-amino acid repeats called apple domains (A1, A2, A3 and A4) and a C-terminal trypsin-like catalytic domain held together by a single disulfide bond between the fourth apple (A4) domains. The functionality, activation pathway and individual domain contributions of FXIa dimer and its interactions with factor IX zymogen are still not well understood.  In this presentation,  the force-field based computational modeling approach was used to understand the structure and dynamics of A4:A4 dimer in solution with the initial model derived from the X-ray crystal structure. The dimer solution structure was developed using explicit-solvent molecular dynamics (MD) simulations. The binding affinity of the dimer is evaluated by MM/PBSA and MM/GBSA methodologies as incorporated into AMBER12 program package. Eight key interacting residues (three charged and three hydrophobic residues) between the A4:A4 dimer interface were subjected to alanine mutagenesis and the structural, dynamic and energetic impact of the mutations in dimer formation is evaluated with reference to wild-type (WT) dimer structure.  The evaluated binding-free energies provide a first-time look at the relative importance of these residues in the dimer formation.

Structure, dynamics, and mutational analysis of Apple-4 dimer interface of human coagulation factor XIa

248th National Meeting (2014)

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