All‐atom structural models of insulin binding to the insulin receptor in the presence of a tandem hormone‐binding element

Abstract

Insulin regulates blood glucose levels in higher organisms by binding to and activating insulin receptor (IR), a constitutively homodimeric glycoprotein of the receptor tyrosine kinase (RTK) superfamily. Therapeutic efforts in treating diabetes have been significantly impeded by the absence of structural information on the activated form of the insulin/IR complex. Mutagenesis and photo-crosslinking experiments and structural information on insulin and apo-IR strongly suggest that the dual-chain insulin molecule, unlike the related single-chain insulin-like growth factors, binds to IR in a very different conformation than what is displayed in storage forms of the hormone. In particular, hydrophobic residues buried in the core of the folded insulin molecule engage the receptor. There is also the possibility of plasticity in the receptor structure based on these data, which may in part be due to rearrangement of the so-called CT-peptide, a tandem hormone-binding element of IR. These possibilities provide opportunity for large-scale molecular modeling to contribute to our understanding of this system. Using various atomistic simulation approaches, we have constructed all-atom structural models of hormone/receptor complexes in the presence of CT in its crystallographic position and a thermodynamically favorable displaced position. In the "displaced-CT" complex, many more insulin-receptor contacts suggested by experiments are satisfied, and our simulations also suggest that R-insulin potentially represents the receptor-bound form of hormone. The results presented in this work have further implications for the design of receptor-specific agonists/antagonists.

Exploring the Conformational Transitions of Biomolecular Systems Using a Simple Two-State Anisotropic Network Model

“…For example, the so-called “string method” based on all-atom MD simulations has been employed successfully to study functionally important conformational transitions in a variety of biological systems, including Src kinases [16], insulin receptor kinase [17], [18], adenylate kinase [19], amyloidogenic isomerization of 2-microglobulin [20], cholesterol flip in membranes [21], myosin VI [22], DNA polymerase [23], and voltage-gated K + channels [3]. Other notable methods that seek to shed some light on the important intermediate structures between experimentally known intermediates include the weighted ensemble method [24]–[27] and dynamic importance sampling [28]–[30].…”

Enhanced Sampling in Molecular Dynamics Using Metadynamics, Replica-Exchange, and Temperature-Acceleration

“…String method has been used to study activation of the insulin-receptor kinase [63], docking of insulin to its receptor [230], and myosin [231]. In these examples, the update of the string coordinates is done at a lower frequency than the atomic variables in each image.…”

Collective Variable Approaches for Single Molecule Flexible Fitting and Enhanced Sampling

“…Vashisth and Abrams also applied TAMD to study conformational change in the C-terminus of the B-chain of insulin (Figure 2) in the insulin/IR complexes. 169 This conformational change exposed residues buried in the core of hormone for it to achieve a tighter registry and higher affinity for IR. Similar to the kinase work, TAMD-generated conformations in this study were also further validated with the help of string method in CVs.…”

“…Some of the terminal residues of CT spontaneously fold/unfold during TAMD trajectories. Adapted with permission from ref (169). Copyright 2013 John Wiley & Sons, Inc.…”