HAMILTONIAN BASED APPROACH TO MODEL IDPS AND THEIR FUNCTION

Protein sequence -- encoding the unique folded structure and consequently function -- plays

a profound role in biological information processing. This central notion, however, appears to

be at odds with Intrinsically Disordered Proteins (IDP)s that lack unique folded structure and

are constantly shuttling between different conformations. Despite their disordered and highly

dynamic nature, in contrast to folded proteins, IDPs have specific conformational features and

critical function. The clues to conformation, function -- and their relation, if any -- must be in

the sequence. But how do we decipher this code from the sequence ? To answer this, we

take a theoretical physics approach starting with a coarse-grain analytically tractable

Hamiltonian that accounts for electrostatic interaction between amino acids that are also

topologically correlated due to chain connectivity (covalent linkage). This formalism --

grounded on tools of equilibrium statistical physics — allows us to unmask several elegant

mathematical formulae hidden in the sequence that describe conformational features of these

disordered proteins. These sequence dependent metrics reveal many surprises in IDP

conformation and yield rules of design. First, they give us ways to manipulate sequences to

cause substantial changes in their conformation. We design sequences to observe such

changes and test these predictions with computer simulation and experiment. At the same

time, we are also studying how messages hidden in these formulae can actually tell us about

the function of these proteins and ultimately help us understand evolution.