Temperature-Accelerated Molecular Dynamics Reveals That Insulin Can Undergo Large-Scale Conformational Reorganization On Binding to Its Receptor

Monday, October 17, 2011: 12:50 PM
Conrad D (Hilton Minneapolis)
Harish Vashisth, Chemistry and Biophysics, University of Michigan, Ann Arbor, MI and Cameron F. Abrams, Drexel University, Philadelphia, PA

Insulin regulates blood glucose levels in higher organisms by
specifically binding to and activating a transmembrane glycoprotein
known as the insulin receptor (IR). Detailed photo-crosslinking
studies have suggested that insulin molecule reorganizes on binding to
IR due to the displacement of its flexible B-chain C-terminus in the
presence of a tandem hormone binding structural motif called
CT-peptide. Although a detailed understanding of how insulin binding
leads to receptor activation remains elusive, our recently proposed
all-atom structural models of insulin/IR complexes provide information
valuable for exploring structure-function repertoire of IR. However,
the large-scale conformational change in the insulin was not studied
in these structural models due to the absence of then-unresolved
CT-peptide, and also the lack of adequate simulation techniques. We
have proposed a new conformational sampling algorithm,
temperature-accelerated molecular dynamics (TAMD) (2010,  PNAS,
107, 4961-4966), that provides an immediate opportunity to use
all-atom simulation to directly address these important gaps in our
understanding of insulin binding to IR. Using a combination of
Metropolis Monte-Carlo (MC) and molecular dynamics (MD) simulations,
we have constructed all-atom structural models of insulin/IR complexes
in the presence of (now-resolved) CT-peptide. We further apply TAMD to
the C-terminus of IR-bound (T and R) insulin molecules at a fictitious
thermal energy of 6 kcal/mol, and observe that while insulin remains
stably-bound to IR, it can undergo large-scale conformational change
in the B-chain C-terminus at ~50-ns time-scale resulting in the
exposure of hidden hydrophobic core of insulin. These results are
significant because we demonstrate at the atomistic-scale for the
first time that insulin molecules can undergo large-scale
reorganization on binding to IR in presence of CT-peptide. Moreover,
we suggest TAMD as a viable simulation technique to study such
large-scale conformational changes in proteins.

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See more of this Session: Multiscale Modeling II
See more of this Group/Topical: Computational Molecular Science and Engineering Forum