Wetting of nonconserved residue-backbones: A feature indicative of aggregation associated regions of proteins

Abstract

Aggregation is an irreversible form of protein complexation and often toxic to cells. The process entails partial or major unfolding that is largely driven by hydration. We model the role of hydration in aggregation using "Dehydrons." "Dehydrons" are unsatisfied backbone hydrogen bonds in proteins that seek shielding from water molecules by associating with ligands or proteins. We find that the residues at aggregation interfaces have hydrated backbones, and in contrast to other forms of protein-protein interactions, are under less evolutionary pressure to be conserved. Combining evolutionary conservation of residues and extent of backbone hydration allows us to distinguish regions on proteins associated with aggregation (non-conserved dehydron-residues) from other interaction interfaces (conserved dehydron-residues). This novel feature can complement the existing strategies used to investigate protein aggregation/complexation.

Aggregation tendencies in the p53 family are modulated by backbone hydrogen bonds

“…Our pressure experiments add a new piece of evidence for this hypothesis. It is also noteworthy that despite importance of identifying these regions, the BHB wrapping results were not obvious based on static structures (similar to the finding reported in45), illustrating the importance of dynamics to unveil molecular detail. The BHB protection patterns reported here provide a basis for evaluating the efficacies of engineered higher stability p53 DBD constructs and identifying sites of structural vulnerability induced by disease-related p53 mutations.…”

“…Underprotected BHBs, commonly referred to as dehydrons, are sticky sites that are often involved in protein associations. For instance, the p53 DBD contains groups of underprotected BHBs at its dimer interface and around residues involved in DNA and protein recognition, which become more protected upon complexation45. Protection of vulnerable BHBs with small molecules has also been demonstrated, with the concept becoming an emerging strategy in drug discovery and design46.…”

The Roles of Water in the Protein Matrix: A Largely Untapped Resource for Drug Discovery

“…Furthermore, the aggregation propensities of Aβ42 mutants and mutants of the N-terminal domain of the HypF protein and of acylphosphatase were found to correlate with protein solvation free energy . Another proposal is that dehydrons, nonconserved residues with unsatisfied H-bonds, might lead to unwelcome protein aggregation …”

“…216 Another proposal is that dehydrons, nonconserved residues with unsatisfied H-bonds, might lead to unwelcome protein aggregation. 217 The third example highlights how dense interfacial water is an essential component in transient protein−ligand interfaces involving electron transfer. The number of water molecules at the PPI of the complex between cytochrome P450cam with putidaredoxin was found to be dependent on the redox state of the system.…”

Biomolecular hydration in protein-protein interaction, protein stability and aggregation and lead optimization : computational studies

“…Structural superimposition was carried out using the "align" function in the PyMOL molecular visualization software (DeLano, 2009). The cap analogue in the different structures of eIF4E consists of an N7 substituted guanosine base and a sugar with an attached monophosphate, diphosphate, or triphosphate moiety (Table 5. 1). Some of the structures also contain a nucleic acid attached to the cap.…”