Prediction of the Effects of the Val66Met Polymorphism and Adjacent Structured Domains on the Conformational Ensemble of an Intrinsically Disordered Protein, Brain-Derived Neurotrophic Factor

Abstract

The discovery of Intrinsically Disordered Proteins (IDP) has challenged the structure-function paradigm and required new approaches for identifying functional mechanisms of proteins. Disease-associated Single Nucleotide Polymorphisms (SNP) are common in the disordered regions of proteins (>21.7 %), but not much is known about their effect on the conformational ensemble. Brain Derived Neurotropic Factor (BDNF) belongs to the family of neurotrophins, and facilitates neurogenesis in its short (mature) form but apoptosis in its long (pro) form. A common (4% US population) SNP that results in the Val66Met mutation in the disordered N terminus domain of the long form of BDNF (proBDNF) has been associated with various neurological and psychiatric disorders. We previously explored the effect of this SNP on likely conformations of the BDNF prodomain, using large-scale fully atomistic replica exchange molecular dynamics simulations of the disordered region, and found significant effects of the single point mutation on the global conformational ensemble. In the present study, we investigate the effects of the presence of the ordered region on this conformational ensemble, as well as the role of the SNP on docking of the disordered prodomain to the ordered region, using fully atomistic Hamiltonian Replica Exchange Simulations. These computational investigations complement previous NMR approaches that were restricted to the isolated prodomain, and serve as model calculations for studying the role of adjacent structured regions on conformations of intrinsically disordered regions.