Alladi Ramakrishnan Hall

The Globular-Disordered Interface in Proteins: Addressing Molecular Evolution from Protein Design

Sankar Basu

Department of Chemistry, University of Delhi (North Campus), Delhi 110007

The emergence of Intrinsically Disordered Proteins (IDPs) in protein science is rather recent compared to the well folded globular proteins. Due to their inherent disorder, they lack well-folded 3D structures in spite of remaining functional throughout their entire lifespan. They, therefore, are represented as stochastic dynamic conformational ensembles rather than single global minima structures, characteristic of the ordered globular proteins. One of the hallmark of IDPs is that they violate the classical view of protein folding, viz., the `one sequence – one structure – one function' paradigm, and, rather map to multi-functional proteins, exhibiting enormous amount of binding promiscuity by keeping enough disorder even in their bound forms. This binding promiscuity of IDPs makes them the causal factors in many deadly human diseases and therefore attractive drug targets. From an evolutionary perspective, they elegantly complement the functional repertoire of primarily uni-functional ordered globular proteins. Though there is not yet a general evolutionary rule regarding the origin of disordered and globular proteins, there have been instances of successful design, for example, of folded globular repeats from their disordered ancestors. The folding of globular proteins is said to be kinetically triggered by a rapid collapse of hydrophobic residues in water, leading to a densely packed interior (core) where the hydrophobic side-chains pack against each other by complementary interlocking, likewise to that of a three dimensional jig-saw puzzle. This is reflected in the attainment of high shape complementarity values (Sm) of the buried side-chains. In addition, they also maintain a global harmony by meticulously balancing electric fields coming from different parts of the folded chain, reflected in their optimum electrostatic complementarity (Em) values. In contrast, IDPs essentially lack the `packing component', primarily due to the deliberate natural placement of hydrophobic residues, in such a manner that inhibit their close gathering and thereby potentially acting against a rapid hydrophobic collapse in an aqueous environment. Rather, they mostly rely on electrostatic interaction as the overwhelmingly major force acting on their dynamics, which naturally arise due to the preponderance and the strategic location of charged and polar residues. In order to remain multi-functional and to exhibit their characteristic binding promiscuity, they need to retain considerable dynamic flexibility. At the same time, they also need to accommodate a large pull of oppositely charged residues, which can potentially lead to the formation of salt-bridges (ionic bonds), imparting local rigidity in them. The formation of salt-bridges are therefore, paradoxical in the context of retaining the desired dynamic flexibility. Hence, there appears to be a meticulous trade-off between the two mechanisms. Unraveling of such a mechanism can potentially facilitate the future design of salt-bridges as a mean to further explore the disordered-globular interface in proteins.
The talk will cover these seemingly contrasting attributes in both globular and disordered proteins, with a major focus on the nature and possible design of salt-bridges in IDPs in order to address the evolutionary origin of intrinsic disorder.