Computational Insights into the Sequence-Activity Relationships of the NGF(1–14) Peptide by Molecular Dynamics Simulations

Abstract

The Nerve Growth Factor (NGF) belongs to the neurothrophins protein family involved in the survival of neurons in the nervous system. The interaction of NGF with its high-affinity receptor TrkA mediates different cellular pathways related to Alzheimer’s disease, pain, ocular dysfunction, and cancer. Therefore, targeting NGF-TrkA interaction represents a valuable strategy for the development of new therapeutic agents. In recent years, experimental studies have revealed that peptides belonging to the N-terminal domain of NGF are able to partly mimic the biological activity of the whole protein paving the way towards the development of small peptides that can selectively target specific signaling pathways. Hence, understanding the molecular basis of the interaction between the N-terminal segment of NGF and TrkA is fundamental for the rational design of new peptides mimicking the NGF N-terminal domain. In this study, molecular dynamics simulation, binding free energy calculations and per-residue energy decomposition analysis were combined in order to explore the molecular recognition pattern between the experimentally active NGF(1–14) peptide and TrkA. The results highlighted the importance of His4, Arg9 and Glu11 as crucial residues for the stabilization of NGF(1–14)-TrkA interaction, thus suggesting useful insights for the structure-based design of new therapeutic peptides able to modulate NGF-TrkA interaction.

BDNF- and VEGF-Responsive Stimulus to an NGF Mimic Cyclic Peptide with Copper Ionophore Capability and Ctr1/CCS-Driven Signaling

“…c-NGF(1−14) lesser flexibility 56 leads to a secondary structure that is different from that of the more flexible linear NGF(1−14). 57 In addition, the PPII helix structure of the C-terminal section favors hydrophobic over electrostatic interactions resulting from the left-handed chirality that, in turn, determines a more rigid structure and renders c-NGF (1−14) binding to the TrkA-D5 receptorspecific. The cyclic peptide shows significantly more resistance to proteases than its linear analogue; the differences in human serum hydrolytic kinetic process can be related to their different secondary structures, which do not affect the interaction with the receptor alone.…”

“…29 Monomeric and dimeric linear peptide fragments containing the NGF Nterminus have been shown to interact with the TrkA-D5 domain, by involving noncovalent interactions between the His residues of mimicking peptides and some His residues present in the TrkA receptor domain. [33][34][35]57 At least His-4 of the cyclic analogue investigated here contributes to the molecular recognition of the specific domain of the NGF receptor. The role of the His residues in the peptide is not restricted to the interaction with the specific domain of the receptor.…”

“…Taken together, our findings suggest that c-NGF(1–14) exerts an NGF-like activity showing a significant activation of specific signaling pathways. c-NGF(1–14) lesser flexibility leads to a secondary structure that is different from that of the more flexible linear NGF(1–14) . In addition, the PPII helix structure of the C-terminal section favors hydrophobic over electrostatic interactions resulting from the left-handed chirality that, in turn, determines a more rigid structure and renders c-NGF(1–14) binding to the TrkA-D5 receptor-specific.…”

“…Furthermore, the protein histidine residues 4 and 8 have been found to play an important role in the biological activity of the NGF N-terminus domain; the point substitution of both His-4 and His-8 by alanine significantly decreases TrkA binding and PC12 neuritogenic activity . Monomeric and dimeric linear peptide fragments containing the NGF N-terminus have been shown to interact with the TrkA-D5 domain, by involving noncovalent interactions between the His residues of mimicking peptides and some His residues present in the TrkA receptor domain. − , At least His-4 of the cyclic analogue investigated here contributes to the molecular recognition of the specific domain of the NGF receptor. The role of the His residues in the peptide is not restricted to the interaction with the specific domain of the receptor.…”

Bioinspired Nanoplatforms Based on Graphene Oxide and Neurotrophin-Mimicking Peptides

“…It is, thus, important to find a way to smoothen the administration pathways of these drugs; the synthesis of peptides able to mimic specific domains of the NTs may represent an alternative to bypass the aforementioned shortcomings [ 47 , 48 , 49 ]. Considering the role of the N-terminal region as the key domain of NTs for the binding selectivity and activation of Trks [ 50 , 51 , 52 ], some of us have synthesized linear peptides encompassing the 1–14 residues of NGF (NGF 1-14) [ 53 , 54 ], the 1–12 residues of BDNF (BDNF 1-12) [ 55 , 56 ], and the 1–13 residues of NT-3 (NT3(1-13) [ 57 ] that displayed activity in the neurite outgrowth and CREB activation [ 58 , 59 ].…”