Unveiling functional motions based on point mutations in biased signaling systems: A normal mode study on Nerve Growth Factor bound to TrkA

Abstract

Many receptors elicit signal transduction by activating multiple intracellular pathways. This transduction may be triggered by a nonspecific ligand, which simultaneously activates all receptor’s signaling paths. In addition, the binding of a biased ligand preferentially elicits one path over another, in a process called biased signaling. Identifying the functional motions related to each one of these distinct pathways have direct impact in the development of new efficient and specific drugs. Here we show how to detect functional motions considering the case of the NGF/TrkA-Ig2 complex. TrkA receptors activation mediated by NGF depends on specific structural motions that trigger neuronal growth, development and survival in nervous system. R221W mutation in the ngf gene impairs the nociceptive signaling. Here we show the wide spread structural effects of this mutation in the NGF/TrkA-Ig2 complex, leading to the deletion of collective motions important to TrkA activation of nociceptive signaling. Our results suggest that subtle changes in the interaction network within neurotrophic factors due to the point mutation are sufficient to inhibit necessary conformational changes for TrkA receptors activation. The methodological approach presented in this article based conjunctively on normal mode analysis and the experimentally observed functional alterations due to point mutations provides an essential tool for unveiling the structural changes and motions related to the disease, that in turn could be important for a drug design study.

HARP: a database of structural impacts of systematic missense mutations in drug targets of Mycobacterium leprae

“…Employing molecular dynamics simulations and normal mode analysis aid accurate assessment of stability changes [16] . However, molecular dynamic simulations are computation and data-intensive and can be complemented to an extent by tools that employ normal mode perturbations [17] . Predicting the consequences of point mutations in leprosy with considerable accuracy and identifying their association with antimicrobial resistance outcomes are essential due to the lack of robust experimental methods of diagnosing resistance.…”