Steric hindrance, and conformations

MOA Blocks Gpllb/llla receptors by steric hindrance and conformation effect Reversible Gpllb/llla inhibitor Reversible Gpllb/llla inhibitor... 

Folding of a peptide probably occurs coincident with its biosynthesis (see Chapter 38). The physiologically active conformation reflects the amino acid sequence, steric hindrance, and noncovalent interactions (eg, hydrogen bonding, hydrophobic interactions) between residues. Common conformations include a-helices and P pleated sheets (see Chapter 5). 

The changes with steric hindrance and temperature must be due to conformational effects along the polymer chains. It is now generally agreed that the thermochromism results from an increase in the proportion of trans- to gauche conformations in the polymer chain as the temperature is decreased. Similarly, the introduction of sterically hindering substituents could increase the amount of trans junctions. Evidence in favor of this model is presented in several recent papers, (28i) as well as the chapter by Michl in this volume. 

Organic chemistry is a very visual subject, but most of us have difficulty visualizing a structure in three dimensions. Making a 3-D model of the structure allows you to detect finer points of conformation, steric hindrance, and so on. Making a model also helps you find those Ccirbons with incorrect numbers of bonds. 

One of the most interesting developments in the stereochemistry of organic compounds in recent years has been the demonstration that trans-cyclooctene (but not the cis isomer) can be resolved into stable chiral isomers (enantiomers, Section 5-IB). In general, a Wa/w-cycloalkene would not be expected to be resolvable because of the possibility for formation of achiral conformations with a plane of symmetry. Any conformation with all of the carbons in a plane is such an achiral conformation (Figure 12-20a). However, when the chain connecting the ends of the double bond is short, as in trans-cyclooctene, steric hindrance and steric strain prevent easy formation of planar conformations, and both mirror-image forms (Figure 12-20b) are stable and thus resolvable. 

For discotic molecules with long alkyl side chains, 2D assembly also often leads to mirror-symmetry-broken structures. In addition to steric hindrance and superlattice formation, the mechanism involves conformational mobility of the side chain [34], This has been shown for the Cu-phathlocyanine derivative CuPcOC8 on hopg using STM (Fig. 13). The C4v-symmetric molecule forms dense layers with interdigitated alkyl chains. This forces the molecules into a rotated structure [35,36]. 

Nitropropane As mentioned in Section 3.9, most open-chain compounds—barring severe steric hindrance—are conformationally mobile at room temperature coupling constants in each set average out and become essentially chemically shift equivalent. Thus a 300 MHz, room-temperature spectrum of 1-nitropropane is described as A3M2X2 rather than A,MM XX, and first-order rules apply (see Figure 3.51). 

Experiments with glyceraldehyde-3-phosphate dehydrogenases from M. fervidus and P. woesei as well as with different mutant enzymes [29] indicate that the peptide chain is largely protected from covalent modification in the native protein conformation. It would appear that the native conformation protects the weak links in the chain against attacking water molecules by steric hindrance and by restricting the torsional freedom of the chain. 

The protein chain in hemoglobin may place restraints on the iron-to-proxi-mal histidine bond. On the other side of the heme, the distal histidine and occluded water molecules may hydrogen-bond to the coordinated dioxygen and force ligands to adopt geometries that are different from those observed in the absence of steric hindrances. The conformation of the porphyrin skeleton may also be perturbed by the protein chain. Clearly, it is the protein chain that bestows the property of cooperativity on oligomeric oxygen carriers. 

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