Role of the Conformational Versatility of the Neurotrophin N-Terminal Regions in Their Recognition by Trk Receptors

Abstract

Neurotrophins (NTs) represent a family of proteins that play an important role in the survival, development, and function of neurons. Extensive efforts are currently being made to develop small molecules endowed with agonist or antagonist NT activity. The structurally versatile N-termini of these proteins are considered regions of interest for the design of new molecules. By combining experimental and computational approaches, we analyzed the intrinsic conformational preferences of the N-termini of two of the most important NTs: NGF (NGF-Nter) and NT4 (NT4-Nter). Circular dichroism spectra clearly indicate that both peptides show a preference for random coil states. Because this finding does not preclude the possibility that structured forms may occur in solution as minor conformational states, we performed molecular-dynamics simulations to gain insights into the structural features of populated species. In line with the circular dichroism analysis, the simulations show a preference for unstructured states for both peptides. However, the simulations also show that for NT4-Nter, and to a lesser extent for NGF-Nter, helical conformations, which are required for binding to the Trk receptor, are present in the repertoire of structures that are intrinsically accessible to these peptides. Accordingly, molecular recognition of NTs by the Trk receptor is accomplished by the general mechanism known as population shift. These findings provide a structural rationale for the observed activity of synthetic peptides based on these NT regions. They also suggest strategies for the development of biologically active peptide-based compounds.