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Molecular Dynamics Simulations of the NGF-TrkA Domain 5 Complex and Comparison with Biological Data

Giovanni Settanni^*, Antonino Cattaneo^* and Paolo Carloni^*,

^* International School for Advanced Studies (SISSA/ISAS); and National Institute for the Physics of Matter-DEMOCRITOS Modeling Center for Research in Atomistic Simulation, 34014 Trieste, Italy

Correspondence: Address reprint requests to Prof. Paolo Carloni, International School for Advanced Studies, via Beirut 2–4, 34100 Trieste, Italy. Tel.: +39-040-3787-407; Fax: +39-040-3787-528; Email: carloni{at}sissa.it.

The nerve growth factor (NGF) is an important pharmacological target for Alzheimer's and other neurodegenerative diseases. Its action derives partly from its binding to the tyrosine kinase A receptor (TrkA). Here we study energetics and dynamics of the NGF-TrkA complex by carrying out multinanosecond molecular dynamics simulations, accompanied by electrostatic calculations based on the Poisson-Boltzmann equation. Our calculations, which are based on the x-ray structure of the complex, suggest that some of the mutations affecting dramatically the affinity of the complex involve residues that form highly favorable, direct or water-mediated hydrogen bond interactions at the ligand-receptor interface and, in some cases, that also critically participate to the large-scale motions of the complex. Furthermore, our calculations offer a rationale for the small effect on binding affinity observed upon specific mutations involving large changes in electrostatics (i.e., the charged-to-neutral mutations). Finally, these calculations, used along with the mutagenesis data, provide a basis for designing new peptides that mimic NGF in TrkA binding function.

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				M. Berrera, A. Cattaneo, and P. Carloni Molecular Simulation of the Binding of Nerve Growth Factor Peptide Mimics to the Receptor Tyrosine Kinase A Biophys. J., September 15, 2006; 91(6): 2063 - 2071. [Abstract] [Full Text] [PDF]