Abstract
The abundance of intrinsic disorder in the protein realm and its role in a variety of physiological and pathological cellular events have strengthened the interest of the scientific community in understanding the structural and dynamical properties of intrinsically disordered proteins (IDPs) and regions (IDRs). Attempts at rationalizing the general principles underlying both conformational properties and transitions of IDPs/IDRs must consider the abundance of charged residues (Asp, Glu, Lys, and Arg) that typifies these proteins, rendering them assimilable to polyampholytes or polyelectrolytes. Their conformation strongly depends on both the charge density and distribution along the sequence (i.e., charge decoration) as highlighted by recent experimental and theoretical studies that have introduced novel descriptors. Published experimental data are revisited herein in the frame of this formalism, in a new and possibly unitary perspective. The physicochemical properties most directly affected by charge density and distribution are compaction and solubility, which can be described in a relatively simplified way by tools of polymer physics. Dissecting factors controlling such properties could contribute to better understanding complex biological phenomena, such as fibrillation and phase separation. Furthermore, this knowledge is expected to have enormous practical implications for the design, synthesis, and exploitation of bio-derived materials and the control of natural biological processes.
Highlights
Disordered proteins (IDPs) and protein regions (IDRs) escape the paradigm of protein folding and must, rather, be described as conformational ensembles of interconverting conformers
When comparing experimental data with predictions inspired to FCR, or more complex composition-based heuristics, collapsed globules turn out to be less frequent than predicted [33,34,35,36]. Possible reasons for these discrepancies could be searched in the weaknesses of either the experimental or the computational approaches: (i) Collapsed globules have higher aggregation propensity compared to expanded coils, hampering structural characterization at the high protein concentrations required for some biophysical techniques (e.g., nuclear magnetic resonance (NMR), small-angle X-ray scattering (SAXS), etc.); and (ii) the efficiency of prediction algorithms could be hindered by the complexity of the intramolecular interactions’ governing compactness, as well as the interplay with the physicochemical environment [37]
Knowledge concerning the role of electrostatics on the structure and function of intrinsically disordered proteins (IDPs)/IDRs benefits from theoretical, experimental, and heuristic contributions from the fields of polymer physics and computational science
Summary
Disordered proteins (IDPs) and protein regions (IDRs) escape the paradigm of protein folding and must, rather, be described as conformational ensembles of interconverting conformers. Nuclear magnetic resonance (NMR) spectroscopy allows measurement of the pH dependence of chemical shifts Such experiments have highlighted that Asp, Glu, and Lys residues in disordered polypeptides, as well as in solvent-exposed regions of ordered proteins [12], have pKa values close to those measured in random coil models [14], with shortand medium-range interactions prevailing on long-range electrostatic ones [15,16]. It is highly basic due to charge delocalization; on the other side, the guanidinium group is a very weakly hydrated cation [17] This latter property facilitates Arg residue burial in hydrophobic micro-environments [18] and its stacking interactions with aromatic protein residues [17,19]. Describing the mathematical formalisms underlying polypeptide structure goes beyond the aims of this review, which is meant to provide an overview of its practical implications of IDP conformational behavior in the field of protein science and cellular biochemistry
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