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Molecular Simulation of the Binding of Nerve Growth Factor Peptide Mimics to the Receptor Tyrosine Kinase A

Marco Berrera ^* , Antonino Cattaneo ^*  and Paolo Carloni ^* 

^* Scuola Internazionale Superiore di Studi Avanzati, Trieste, Italy; Istituto Nazionale per la Fisica della Materia, Democritos Modeling Center for Research In Atomistic Simulation, Trieste, Italy; and European Brain Research Institute, Rome, Italy

Correspondence: Address reprint requests to P. Carloni, Tel.: 39-040-378-7407; E-mail: carloni{at}sissa.it.

Nerve growth factor (NGF) mimics play an important role for therapies that target the receptor tyrosine kinase A (trkA). The N-terminal fragment of the NGF (N-term@NGF) was previously demonstrated to be an important determinant for affinity and specificity in the binding to trkA. Here we use a variety of computational tools (contact surface analysis and free energy predictions) to identify residues playing a key role for the binding to the receptor. Molecular dynamics simulations are then used to investigate the stability of complexes between trkA and peptides mimicking N-term@NGF. Steered molecular dynamics calculations are finally performed to investigate the process of detaching the peptide from the receptor. Three disruptive events are observed, the first involving the breaking of all intermolecular interactions except two salt bridges, which break subsequently.