Alpha rotamer

If the sequence of a protein has more than 90% identity to a protein with known experimental 3D-stmcture, then it is an optimal case to build a homologous structural model based on that structural template. The margins of error for the model and for the experimental method are in similar ranges. The different amino acids have to be mutated virtually. The conformations of the new side chains can be derived either from residues of structurally characterized amino acids in a similar spatial environment or from side chain rotamer libraries for each amino acid type which are stored for different structural environments like beta-strands or alpha-helices. 

Cannon, in 1975, suggested that dopamine might bind to Its receptors in two possible conformational extremes, which he designated the "alpha" and "beta" rotamers, XIa and Xlb, respectively (20). In this view apomorphine would represent a structure containing a dopamine fragment "frozen" into the alpha rotameric form. By contrast, 6,7-ADTN contains a dopamine moiety constrained in the beta rotameric form. In both cases the side chain is nearly coplanar with the aromatic ring and is... 

The close structural similarity of the semirigid conformational analogue 1 to the trans-rotamer of dopamine (DA) was noted almost ten years ago (1,2). The synthesis of 1 has been described more recently and its pharmacological profile determined (3-6) to be similar to alpha-methyldopamine (AMDA) which is inactive as a dopaminergic agent. 

The authors assume this reflects the rotamer population of the zwitterionic intermediate and that 51 arises by abstraction of an equatorial proton (Scheme 36). However, this would be more likely to occur via a twist conformation which could arise, at least in part, from equatorial attack on the enamine. Interestingly the tetrasubstituted enamine (51) crystallized from the reaction mixture and was shown on heating in benzene, without added acid catalyst, to revert to the same mixture of 51 and 52. This presumably reflects the greater carbon acidity of a methylene alpha to a sulphone group which can therefore catalyse the interconversion or cause reversion to enamine followed by re-alkylation100. 

The two protons on the beta carbon (Cp) are labeled Hpj and Hp2, and the proton on the alpha carbon (CJ is labeled H ,. Although Hpi and Hp2 may at first appear to be identical—especially if we draw the molecule in two dimensions—the three Newman projections showing the rotamers resulting from rotation about the Cp—C , bond reveal that the beta protons do not experience the same chemical environment. 

It was found that structures with up to 14 rotatable bonds are readily handled using the rule-based conformational analysis 2 (conjugated and double bonds), 3 (single bonds), and 4 (sp -sp bonds) rotamers per bond were calculated in the databases for such structures. The default for alpha (sp -sp ) bonds in Chem-X is a 6-point analysis, but 4 points can offer a large gain in time without necessarily a reduction in yield. The number of points is based on the increment of rotation about a particular bond and equals 360° per rotational increment. Thus a 60° increment would equal a 6-point bond. For a corporate database of 62,000 company compounds, a total of 29 million conformations were accepted by the rules from a total of 912 million considered... 

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