Criticality in the conformational phase transition among self-similar groups in intrinsically disordered proteins: Probed by salt-bridge dynamics

Abstract

Intrinsically disordered proteins (IDP) serve as one of the key components in the global proteome. In contrast to the dominant class of cytosolic globular proteins, they harbor an enormous amount of physical flexibility and structural plasticity enforcing them to be retained in conformational ensembles rather than well defined stable folds. Previous studies in an aligned direction have revealed the importance of transient dynamical phenomena like that of saltbridge formation in IDPs to support their physical flexibility and have further highlighted their functional relevance. For this characteristic flexibility, IDPs remain amenable and accessible to different ordered binding partners, supporting their potential multi-functionality. The current study further addresses this complex structure-functional interplay in IDPs using phase transition dynamics to conceptualize the underlying (avalanche type) mechanism of their being distributed across and hopping around degenerate structural states (conformational ensembles). For this purpose, extensive molecular dynamics simulations have been done and the data analyzed from a statistical physics perspective. Investigation of the plausible scope 'selforganized criticality' (SOC) to fit into the complex dynamics of IDPs was found to be assertive, relating the conformational degeneracy of these proteins to their multi-functionality. In accordance with the transient nature of 'salt-bridge dynamics', the study further uses it as a probe to explain the structural basis of the proposed criticality in the conformational phase transition among self-similar groups in IDPs. The analysis reveal scale-invariant self-similar fractal geometries in structural conformations of different IDPs. Also, as discussed in the conclusion, the study has the potential to benefit structural tinkering of bio-medically relevant IDPs in the design of biotherapeutics against them.

Capturing a crucial ‘disorder-to-order transition’ at the heart of the coronavirus molecular pathology – triggered by highly persistent, interchangeable salt-bridges

“…Based on present knowledge and understanding, the revealed transition together with the disorder, intrinsic to the CoV-2 FLCS Spike [21] should find its place at the very heart of the coronavirus molecular pathology. We further demonstrate that the involved 'disorder-to-order transition' in CoV-2 is triggered and sustained by highly persistent interchangeable salt-bridge dynamics -which is often characteristic to protein disorder transitions [49,50]. We also present a novel application of the legendary Ramachandran Plot [51] in probing the said 'transition' at the CoV-2 Spike-Furin interface.…”

“…Further, from this interfacial contact map, ionic bonds / salt-bridges were identified following standard definitions and computational techniques [49,50,86,87]. To that end, those inter-residue contacts were assembled and characterized as salt-bridges / ionic bonds where two oppositely charged side chain heavy atoms, a nitrogen (N + ) and an oxygen (O -), coming from two different amino acid residues from the two molecular partners (Spike and Furin) were found within 4.0 Å of each-other.…”

“…Following standard analytical methods [49,50], first, all unique salt-bridges occurring at least once in the MD simulation trajectories were identified and accumulated. The dynamic persistence (pers) of each unique (non-redundant) salt-bridge was then calculated as the ratio of the number of structural snapshots to which the salt-bridge was found to form with respect to the total number of snapshots sampled (at regular intervals) in the trajectory.…”

“…In both ensembles, dynamic and static, the identification of saltbridges were followed by their individual survey and also a statistical analyses of dynamic or static 'ensemble descriptors of salt-bridges' (e.g., persistence/occurrence and average contact intensities; see section 2.5.2, Materials and Methods). Together these parameters can effectively be used to decipher and interpret the complex nature of salt-bridge dynamics associated with protein disorder transitions [49,50]. One of the trademark features of salt-bridge dynamics associated with disorder transitions is a trade-off or an optimal balance between transience and persistence of salt-bridges which serves to sustain a disordered state while a shift of this balance leads to disorder transitions [49,50].…”

Folding and self-assembly of short intrinsically disordered peptides and protein regions

“…1F0R and Ab42 both had appropriate diverse structural phases with a substantial self-similarity among the conformational phases. 157 Optimized potentials for liquid simulations (OPLS)…”