Biophysical mechanisms of intrinsic protein disorder: lessons from a protein backbone model
Drake, Justin Alexander
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Intrinsically disordered regions (IDRs) in proteins populate a dynamic, heterogenous ensemble of structures. Proteins involved in the regulation of critical cellular functions rely on IDRs to carry out their functions. IDRs have been implicated in a number of diseases for which there are currently no treatments. To successfully target drugs to IDRs, a quantitative description of the biophysical mechanisms that dictate the properties of IDRs is needed. In this dissertation, we take a computational approach to study the thermodynamics, particularly free energy and entropy, that drive the collapse and aggregation of short IDRs as well as the mechanisms underlying structural transitions. To investigate these phenomena, we use a protein backbone model (i.e. oligoglycine) that has been experimentally and computationally shown to exhibit IDR characteristics. Our results suggest that the chain length dependent collapse and aggregation of oligoglycine are due to intra-peptide interactions out-competing favorable peptide-solvent interactions, rather than an entropic or hydrophobic solvation penalty. We propose that the collapse and aggregation of IDRs devoid of hydrophobic residues are due to the same biophysical mechanisms, which should be viewed through the lens of solubility as opposed to classical hydrophobicity arguments. Additionally, we find that the protein backbone innately resists folding, or is poised for disorder, in part because of significant, absolute conformational entropy and favorable solvation free energy. The calculations presented suggest that this substantial conformational entropy of the protein backbone represents a reservoir in which free energy can be withdrawn or deposited as conformational entropy through IDR structural transitions.