Insulin molecular modelling

Jimenez et al. (2002) proposed a molecular model for the insulin protofilament based on these data and on electron cryomicroscopy (cryo-EM) reconstructions of insulin fibrils. The fibrils show a number of twisted morphologies that seem to be alternative packings of similar protofilaments. The protofilaments have cross sections of 30x40 A. The authors suggest a complete conversion to / -structure and model the amyloid monomer as having four jS-strands (Fig. 3B). Each insulin chain contributes two of these jS-strands, and the chains align in a parallel stack, constrained by the interchain disulfide bonds. One pair of stacked /i-stran ds is curved... 

As AIDS research continued, the focus shifted to study of HIV protease. The crystallographic structure of HIV-1 was determined by Tom Blundell (1942- ) and coworkers at Birkbeck College in London in 1989. Blundell had studied under Dorothy Hodgkin, the Nobel laureate who solved the structures of penicillin, insulin, and vitamin B12. Study of the active site of HIV-1 protease combined with molecular modeling enabled the design of the family of protease inhibitors, the new anti-HIV drugs of the 1990s and beyond. 

The opposite page presents models of insulin, a small protein. The biosynthesis and function of this important hormone are discussed elsewhere in this book (pp.l60,388). Monomeric insulin consists of 51 amino acids, and with a molecular mass of 5.5 kDa it is only half the size of the smallest enzymes. Nevertheless, it has the typical properties of a globular protein. 

Cytochrome and insulin are not unique in their opposition to the Darwinian model of genealogy. Relaxin, a hormone of parturition in placental mammals, shows clearly that molecular structures and branching patterns do not connect. When the sequence data of all known relaxins are reviewed, several startling observations could be made. The hormone differs by about 55% in animals of purportedly... 

Furthermore, the neo-Darwinian hypothesis says that the insulin gene had been duplicated long ago and that the left-over copy has mutated into a relaxin.6 Once the astronomical number of mutations had led to an active relaxin any further mutation that would hit the invariant positions would have killed or severely handicapped the owner of that hormone, and therefore all constant residues are important. My colleague Dr. Erika Biillesbach has developed an ingenious as well as practical way to synthesize relaxin and insulin for our NIH-funded research.3 These derivatives allowed us to experimentally test some of the postulated mechanisms in the Darwinian model of molecular evolution. 

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