G-protein coupled receptors (GPCRs) are thought to be proteins with 7-membered transmembrane helical bundles (7TM proteins). Recently, the X-ray structures have been solved for two such proteins, namely for bacteriorhodopsin (BR) and rhodopsin (Rh), the latter being a GPCR. Despite similarities, the structures are different enough to suggest that 3D models for different GPCRs cannot be obtained directly employing 3D structures of BR or Rh as a unique template. The approach to computer modeling of 7TM proteins developed in this work was capable of reproducing the experimental X-ray structure of BR with great accuracy. A combination of helical packing and low-energy conformers for loops most close to the X-ray structure possesses the r.m.s.d. value of 3.13 A. Such a level of accuracy for the 3D-structure prediction for a 216-residue protein has not been achieved, so far, by any available ab initio procedure of protein folding. The approach may produce also other energetically consistent combinations of helical bundles and loop conformers, creating a variety of possible templates for 3D structures of 7TM proteins, including GPCRs. These templates may provide experimentalists with various plausible options for 3D structure of a given GPCR; in our view, only experiments will determine the final choice of the most reasonable 3D template.

Sets of low-energy structures were determined by energy calculations for two cyclic analogues of enkephalin (Ek),

Conformationally restricted cyclic analogues of angiotensin II (ANG II), Aspl-Arg2-ValLTyr4-ValS-His6-Pro 7-Phe 8, with a link between positions 3 and 5 have considerable biological activity. It is proposed that the spatial arrangement of the pharmacophore groups of Tyr a, His 6 and Phe 8 side chains and the C-terminal carboxyl group in ANG II and active analogues is similar. Conformational analysis of ANG II and two cyclic analogues c[Sar ~, Lys3,GIuS]ANG II and c[Sarl,Hcy3,Mp:]ANG II was performed, and a geometrical comparison of the low-energy conformations of these compounds allowed one to propose a model of receptor-bound conformation in terms of the spatial arrangement of the pharmacophore groups. This model is characterised by the close spatial location of the His6-Phe 8 side chains and the Tyr 4 C-terminal carboxyl group and is stabilised by the electrostatic interaction of Arg z and the C-terminal carboxyl group.

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Conformational possibilities of a series of deoxyguanosine analogues possessing or lacking antiviral activity were evaluated using methods of the molecular mechanics. Comparison of the spatial structures of acyclic analogues with one another and with the spatial structures of deoxyguanosine demonstrates restricted conformational mobility for compounds devoid of activity. The level of sterically allowed superposition of functional groups from the acyclic moieties of analogues and the corresponding atomic centres of deoxyribose could serve as a criterion of activity. The superposition could be performed in two different ways through either of the nonhydrogen substituents at the C1' atom in the five-membered ring.