Prediction of the Effects of the Val66Met Polymorphism 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 forced us to find new ways for identifying functional mechanisms of proteins. Studies show that IDPs can function while being partly disordered or may fold once they bind to their receptors. Disease-associated Single Nucleotide Polymorphisms (SNP) are common in the disordered regions of proteins, but not much is known about their effect on the protein structure. Brain Derived Neurotrophic 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 (found in 4% of the United States 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 neuropsychiatric disorders such as bipolar disorder and Parkinson's and Alzheimer's diseases. In order to explore the effect of this SNP on protein structure and dynamics, we conducted Molecular dynamics simulations to identify the effect of the above SNP on likely conformations of proBDNF. Although IDPs have been identified to change their conformations rapidly, many also exhibit some residual secondary structure, which might be biased towards the bound conformation. To construct the ensemble of proBDNF in both forms, large-scale fully atomistic replica exchange calculations of both the Val and Met forms of proBDNF were carried out. We find significant differences in the secondary structure available to Val and Met forms of the protein in the region surrounding the SNP, with results that agree with recent NMR studies. This suggests a position specific residue-type dependence of the residual secondary structure of proBDNF, which might account for functional compromise.