Why Ensemble allosteric model so important?
The increasing use of recombinantly expressed therapeutic proteins in the pharmaceutical industry has highlighted issues such as protein drug stability during long-term storage and effective delivery methods that avoid adverse immunogenic side effects. Controlled chemical modifications, such as substitution, acylation, and PEGylation, have fulfilled some but not all of their promise, while hydrogels and lipid-based formulations can be developed into generic delivery systems.
Strategies to prevent protein aggregation and misfolding during storage may benefit from the recent increase in interest in protein fibrillation. This may lead to generally accepted guidelines and tests to avoid unexpected adverse effects in drug delivery.
Drug resistance
Antimicrobial Resistance In nature, microbes continuously evolve to overcome antimicrobial compounds produced by other microorganisms. The human development of antimicrobial drugs and their widespread clinical use simply provided another selective pressure that encouraged further evolution.
Several important factors can accelerate the evolution of protein drug resistance. These include overuse and misuse of antimicrobials, inappropriate use of antimicrobials, subtherapeutic doses, and patient noncompliance with the recommended course of treatment. Exposure of a pathogen to an antimicrobial compound can select chromosomal mutations that confer resistance.
It can be transmitted vertically to subsequent microbial generations and eventually become predominant in a microbial population that is repeatedly exposed to antimicrobials. Alternatively, many genes responsible for drug resistance are found on plasmids or transposons that can be easily transferred between organisms by horizontal gene transfer.
Ensemble allosteric model and its importance
Allostery is an important regulatory phenomenon enabling precise regulation of biological functions. Early understanding of allostery was gained from seminal work on conformational changes exhibited by structural proteins. Protein allostery has also been shown to occur in intrinsically disordered proteins over the past decade. This emerging concept of disorder-mediated allostery is usefully understood in the context of a thermodynamic ensemble.
● The advantage of this ensemble allosteric model is that it integrates the interpretation of allostery occurring between structured and disordered proteins.
● A central finding from this model is that energetic coupling, the transmission of a signal between individual regions of a protein, is maximized when one or more domains are disordered. This is due to a disorder-order transition that adds additional binding energy to the allosteric system by forming a molecular interaction surface or interface.
● A second finding is that multiple interfaces can constructively or destructively interfere with each other, leading to a new form of allosteric regulation called ‘energetic frustration’. Articulating protein allostery in terms of thermodynamic ensembles allows the formulation of experimentally testable hypotheses that can enhance fundamental understanding and direct drug-design efforts.
These concepts are illustrated here with the specific case of the human glucocorticoid receptor, a medically important multi-domain allosteric protein that contains both structured and disordered regions.