(156c) Molecular Simulation Studies of Insulin Binding to the Insulin Receptor

The hormone insulin regulates blood glucose in higher organisms by

binding to and activating the insulin receptor (IR), a homo-dimeric

glycoprotein of the receptor tyrosine kinase (RTK) superfamily.

Although a detailed understanding of how insulin binding leads to

receptor activation remains elusive, a recently published crystal

structure of the extracellular fragments provides information valuable

for exploring structure-function repertoire of IR. We observed that

neither binding pocket of the crystal structure permits steric

accommodation of an intact insulin monomer. Hence, we subjected the

crystal structure to relaxation via molecular dynamics (MD)

simulations. We report here the results of ≈130 ns of explicit

solvent all-atomistic MD simulations of apo as well as T and R-insulin

docked structure of IR. On equilibration via MD, we observe that

subtle fluctuations in the inter-domain hinge angles lead to

variations in intermonomer buried surface area triggering an

asymmetric relaxation of the IR ectodomain. This asymmetry further

results in opening of one of the two equivalent insulin binding

pockets and closing of its partner. Our results support the notion

proposed by a recent "harmonic-oscillator" model of the receptor

that apo-IR structure can be driven to asymmetric states in solution

with small thermal fluctuations. The results are significant because

we demonstrate successful docking of intact insulin molecules (T and

R) in to the relatively open binding pocket for the first time. Most

importantly, our docking predicted "site 2" residue contacts for

each insulin with the fibronectin loops of the IR ectodomain which

have been confirmed by a recent mutagenesis study.