Fig. (1). A Schematic of native and fibril states formation. It highlights the structural and functional differences of the two states.
Fig. (2) Unification of energy landscape for the formation of native and fibril states of proteins.
Within the cell, proteins are continuously formed as linear chains of amino acids using DNA as a template for the sequence. For the protein to become functional, the chain must fold into the low energy 3-dimensional native state. However, the protein can also acquire an alternate aggregated state of lower energy called the fibril state. The fibril state is associated with a number of human diseases like the Alzheimer's disease, Parkinson's disease, type2 diabetes etc.
From a critical analysis of the literature, researchers at UM-DAE Centre for Excellence in Basic Sciences (CEBS), Indiafound that all the folding equilibrium states such as native like state, molten globule, premolten globule or unstructured state have a tendency to associate with other molecules of similar structure to form the fibril state. They also noticed that the amyloid state is the most stable thermodynamic state present in the energy landscape, whereas native state is a metastable state. On the basis of these analyses, they proposed that exposure of relevant peptide sequences/nucleating sites is the requirement for amyloid fibril formation. They also hypothesized that the native State is just a 'fortunate trap' in the Journey of a protein to its destination, the fibrillar state.
Dr Basir Ahmad, Principal Investigator of the Biophysical Chemistry Lab at CEBS explains
The biologically functional form, 'the native state' and folding intermediate states were found to convert into its primordial ground state, amyloid fibril even under physiological condition through structural fluctuations. If the fibril state is thermodynamically more stable than the native state, then it is only the kinetic barriers that prevent spontaneous folding of proteins into fibril state. So, it seems logical to unify folding and aggregation energy funnel.
However, given the difficulty in the determination of thermodynamic stability of the fibril state due to lack of proper theoretical considerations and methodology, Dr Basir concludes that the idea of a fortunate kinetic trap for the native state is sanguine.