Molecular Dynamics Simulation Analysis of P12 Peptide Interaction with a Hydrophobic, Carbon Fluoride Surface

Excessive fibrin fiber formation on surfaces can lead to thrombosis and stroke. To address this, we study P12, a 14-residue peptide that has been found to reduce fiber formation and clotting. In vivo, adding P12 to a hydrophobic surface leads to considerably reduced fibrin formation. We aim to replicate this process in silico to uncover the atomistic interactions driving P12’s binding to hydrophobic surfaces and identify the properties, such as hydrophobicity, that influence its binding preferences. We further compare these interactions to those between P12 and specific domains of fibrinogen (N-terminal of αC, E, and D).

A fluorinated hydrocarbon surface was constructed using GROMACS and CHARMM-GUI to model the hydrophobic surface. P12 was placed in “face up” and “face down” orientations on the slab, and molecular dynamics simulations were conducted for 100 ns using the CHARMM36 force field and TIP3P water model.

Binding free energy calculations determined the strength of the P12-surface interaction, with a value of -22.45 ± 5.88 kcal/mol for the face-up complex. Analysis of SASA and hydrogen bonding suggested similar stability across orientations, while residue contact analysis revealed strong hydrophilic and hydrophobic contributions. Comparing these results with our simulations on P12 with the domains of fibrinogen, we found that P12 exhibited the strongest affinity for the N-terminal.