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.

The Inorganic Side of NGF: Copper(II) and Zinc(II) Affect the NGF Mimicking Signaling of the N-Terminus Peptides Encompassing the Recognition Domain of TrkA Receptor

“…In these regards, the N-terminal domain of NGF has been disclosed as essential for the stability of the NGF/TrkA complex (Berrera et al, 2006), where the formation of H-bonds at the protein−protein interface stabilized the functional NGF/TrkA-D5 binding (Settanni et al, 2003). …”

The inorganic perspectives of neurotrophins and Alzheimer's disease

“…2). Settanni et al identified a key role for the residues lying at the ligand-receptor interface [136]. These include His4, Glu11, Trp 21, Arg 59, Arg103 of NGF, Glu 295, Phe 303, Arg347, Asn 349, and Gln 350 of TrkA receptor [136,137].…”

“…Settanni et al identified a key role for the residues lying at the ligand-receptor interface [136]. These include His4, Glu11, Trp 21, Arg 59, Arg103 of NGF, Glu 295, Phe 303, Arg347, Asn 349, and Gln 350 of TrkA receptor [136,137]. In particular, the His 4 and Glu 11 residues provide highly persistent H-bond interactions with the receptor, as well as Ile 6 and Phe 7 residues stabilize the binding of the N-term of NGF to TrkA through hydrophobic interactions [137].…”

“…In particular, the His 4 and Glu 11 residues provide highly persistent H-bond interactions with the receptor, as well as Ile 6 and Phe 7 residues stabilize the binding of the N-term of NGF to TrkA through hydrophobic interactions [137]. Moreover, these residues are not conserved along the neurotrophin family, providing specificity for the NGF-TrkA binding [136].…”

Conformational Rigidity within Plasticity Promotes Differential Target Recognition of Nerve Growth Factor

“…Only in the hNGF/TrkA complex (Wiesmann et al, 1999; Wehrman et al, 2007) and in one of the two protomers of a complex with a DNA aptamer (Jarvis et al, 2015), is the N-terminus defined and folded in an α-helix. The generally accepted view is thus that the N-terminus is disordered in the NGF unbound state (Settanni et al, 2003; Berrera et al, 2006). Similar conclusions have been recently reached as result of CD and NMR solution studies and molecular dynamics simulations on two linear hNGF N-terminus peptides (Stanzione et al, 2010; Travaglia et al, 2015).…”