Welcome to the Protein Structure-Function-Dynamics Lab



To perform their specific functional activities, the majority of proteins should fold into distinct three-dimensional conformations. However, the biologically active conformation of a protein is generally found to be marginally stable than the other conformations that the chain can adopt. These marginally unstable protein sequences lead to misfolded species which might end up creating toxic aggregates (oligomeric and fibrillar deposits). Cells regulate protein aggregation via a large-scale protein homeostasis/proteostasis system that stabilizes the misfolding proteins and hence prevents their aggregation. As we grow older, these defence systems lose their capability which eventually results in aggregate deposition diseases. The field of protein aggregates has gained major scientific interest as it plays key roles in a multitude of human diseases. To inhibit aggregation-related diseases, the focus should be given to the identification of the molecular mechanisms and influential potencies involved in the misfolding and subsequent association. 



While considerable developments have lately been made regarding the interpretation of the conformations of amyloid fibrils at a molecular level, most of the intricacies are still unknown regarding the assembly of the amyloid protofibrils and unstructured aggregates that precede their formation and are expected to play an important function in the pathogenesis of protein deposition diseases. The projected number of dementia patients (80 million by 2040), the annual expenditure for brain disorder diseases ($3.5 billion), the rise of deaths due to dementia and Alzheimer’s, and the failed clinical trials at the recent past, have acted as prime motivations for this research plan.


The great significances of this work can be exemplified by a projection. Many crucial misfolding-prone disease-causing protein sequences are currently being studied extensively. The complete role of these studies in a conclusive understanding of a generalized mechanism is at present unclear, however, if the primary role of these studies is to promote drug design, then the focus should be concentrated on the initial and intermediate levels of the aggregation process where nucleation still occurs, and a less structured conformational space should be investigated in the quest for the druggable target(s). The arrangement of proteins within matured fibrillar structures broadly involves cross-β-sheet assemblies, which made them the most popular drug target in the recent past. However, conformational variability is prominent in the fibrillar structures of different proteins, and that might be the reason behind the failure of multiple clinical trials by leading pharmaceutical companies who focused on the fibrillar structure as the druggable target. This is a single extrapolative instance – but one might also imagine answering the following queries:

Monomers – Destabilized Aggregation-Prone State or Interconverting Conformations?

Oligomers – (In)soluble? (Dis)ordered aggregates?

Protofibrils – how many monomers? spherical or chainlike or annular?

Effects - Length, Hydrophobicity, Electrostatics, Mutation, Temperature, Surface, Membrane

Kinetics – Nucleus, Common aggregation intermediate?

Mechanism – Template-irected or seeded polymerisation?

Prediction of Clinical Observables - Age of Onset/Survival Time/ Age of Death

Drugs - Small Molecule-Based or Conjugate Peptide-Based?