title: Molecular dynamics simulations of the NGF-TrkA domain 5 complex and comparison with biological data.
abstract: 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.
authors.affiliation: International School for Advanced Studies (SISSA/ISAS), Trieste, Italy.
authors.forename: Giovanni
authors.initials: G
authors.lastname: Settanni
authors.forename: Antonino
authors.initials: A
authors.lastname: Cattaneo
authors.forename: Paolo
authors.initials: P
authors.lastname: Carloni
mesh_terms: D001665:Binding Sites; D003198:Computer Simulation; D004735:Energy Transfer; D006801:Humans; D006860:Hydrogen Bonding; D046911:Macromolecular Substances; D008958:Models, Molecular; D009038:Motion; D020932:Nerve Growth Factor / Q000737:chemistry*; D011485:Protein Binding; D011487:Protein Conformation; D017434:Protein Structure, Tertiary; D020917:Receptor, trkA / Q000737:chemistry*; D012996:Solutions / Q000737:chemistry; D055672:Static Electricity; D014867:Water / Q000737:chemistry*
chemical_list: D046911:Macromolecular Substances; D012996:Solutions; D014867:Water; D020932:Nerve Growth Factor; D020917:Receptor, trkA