PubMed · 4491246
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E Standl. 1973-08-15. [Insulin].. https://pubmed.ncbi.nlm.nih.gov/4491246/
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Molecular dynamics simulations were carried out on an insulin crosslinked between the N-terminal A chain and the C-terminal B chain to form a so-called mini-proinsulin: N alpha-A1-N epsilon-B29-diaminosuberoyl insulin (DASI). To investigate the influence of crosslinking on the dynamics of the insulin moiety, the bridge was removed from a transient DASI structure and simulation was carried on independently with the then unlinked (ULKI) as well as with the crosslinked species. The effects of crystal packing and quaternary interactions were checked by simulating both types of monomers and dimers known from the hexamer structure. All simulations were compared to previous ones of native insulin. DASI shows general similarity to the native simulations in most parts of the structure. Deviations are visible in the segments to which the bridge is directly connected, i.e. their flexibility is reduced. Upon removal of the bridge the ULKI simulations reapproach those of native insulin. The influence of the bridge spreads over the whole molecule, but all of its main structural features remain intact. The simulations suggest that the displacement of the C-terminal B chain of native insulin, considered important for receptor interaction, is prevented by the bridge, which also partially shields some binding residues. This is in accordance with the poor biological potency of A1-B29-crosslinked insulins.
Hexameric insulin has been crystallized from different conditions in a variety of crystalline modifications. In the presence of approximately 1% phenol and at a pH of 8.5, a new rhombohedral form is produced, space group R3, a = 79.92A and c = 40.39A, in which the asymmetric unit consists of a dimer. The structure has been solved and refined, using data between 8.0 and 2.5A resolution, to a residual of 0.157. The two monomers in the asymmetric unit have nearly identical R conformations, that is, residues B1 through B8 are alpha-helical, producing a continuous alpha-helix from B1 through B19. A phenol molecule is hydrogen bonded to the carbonyl oxygen of A6 Cys of each monomer. Small differences in conformation and the final (2Fo-Fc) and difference electron density maps suggest that an additional phenol molecule is coordinated to one of the two zinc ions.
Comparisons of atomic models for chemically identical protein molecules solved in differing crystal environments provide information on flexibility in the protein structure. The structures of five T4 lysozyme proteins in differing crystal environments showed large relative displacements of the two domains with conserved backbone conformations that are connected by a flexible hinge (H. R. Faber and B. W. Matthews. 1990. Nature (Lond.). 348:263-266). In contrast, my comparison of the positions of all the atoms in two crystal forms of insulin shows that the structural changes caused by the differing crystal contacts are contained within nearby amino acids and are not propagated through the core of the insulin molecule. Groups of atoms that are most significantly displaced are not shifted in large rigid units but are repacked into new and distinct conformations. The transmission of displacements through the single domain insulin molecule is, like the movements due to thermal vibrations (D. L. D. Caspar, J. Clarage, D. M. Salunke, M. S. Clarage. 1988. Nature (Lond.). 332:659-662), characterized by short-range interactions between small atomic groups.