Unraveling the distinct motion bias of TrkA-NGF complex in NGFR100W-driven HSAN V disease

Nerve growth factor (NGF), which binds to tropomyosin-related kinase A (TrkA) receptor, plays essential roles in neuronal survival and function and is also a potent mediator of pain sensation. Mutations in NGF, particularly NGFR100W, cause hereditary sensory autonomic neuropathy V (HSAN V), which is characterized by insensitivity to pain but without impairment of neurotrophin function. Even though several studies reported the mechanism of growing HSAN V disease, the dynamic mechanisms that dictate its functional specificity remain unclear. In this study, we performed a microsecond scale molecular dynamics (MD) simulation to elucidate the changes in the structural dynamics of NGF by NGFR100W at an atomic level to dissect the distinct motion bias for specific TrkA functions. We found that the NGFR100W reduced NGF dimerization while its binding to the TrkA remained unchanged. NGFR100W enhanced the magnitude of bond formation in the different regions from TrkA, which induced different correlated and dynamic motions associated with impaired nociceptive signaling. The dynamics scenario from this study, shedding light on the deleterious role of NGFR100W, provides new structural insights into the function-oriented dynamics motion of the TrkA-NGF complex, offering potential avenues for designing new therapeutics.