Abstract
Proteins are heteropolymers that play important roles in virtually every biological reaction. While many proteins have well-defined three-dimensional structures that are inextricably coupled to their function, intrinsically disordered proteins (IDPs) do not have a well-defined structure, and it is this lack of structure that facilitates their function. As many IDPs are involved in essential cellular processes, various diseases have been linked to their malfunction, thereby making them important drug targets. In this review we discuss methods for studying IDPs and provide examples of how computational methods can improve our understanding of IDPs. We focus on two intensely studied IDPs that have been implicated in very different pathologic pathways. The first, p53, has been linked to over 50% of human cancers, and the second, Amyloid-β (Aβ), forms neurotoxic aggregates in the brains of patients with Alzheimer’s disease. We use these representative proteins to illustrate some of the challenges associated with studying IDPs and demonstrate how computational tools can be fruitfully applied to arrive at a more comprehensive understanding of these fascinating heteropolymers.
Highlights
Proteins are heteropolymers that play essential roles in virtually all biological processes
Given the essential role that protein motion plays in biology, discussions about protein structure should ideally revolve around the structural ensemble of thermally accessible states that a given protein can adopt [9]
intrinsically disordered proteins (IDPs) play a central role in many cellular processes, as their disordered nature provides them with the ability to bind many partners, thereby regulating many biochemical processes
Summary
Proteins are heteropolymers that play essential roles in virtually all biological processes. 40% contain an intrinsically disordered region (IDR) of at least 30 amino acids in length [10,11,12] These proteins have been found to play essential roles in many pathological processes. P53 is a large (393 residues), intracellular, multi-domain protein that has a folded DNA binding domain in addition to several long intrinsically disordered regions (IDRs) These IDRs facilitate its role as a hub in cellular stress networks. Aβ is a small (around 40 residues) fully disordered extracellular protein that may play a role in memory and learning [28] and does not contain any folded subdomains in its monomeric state These proteins have very different structural properties, computational methods have been used to improve our understanding of both of these systems
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