This study presents different procedures for ab initio modeling of peptide loops of different sizes in proteins. Small loops (up to 8–12 residues) were generated by a straightforward procedure with subsequent “averaging” over all the low‐energy conformers obtained. The averaged conformer fairly represents the entire set of low‐energy conformers, root mean square deviation (RMSD) values being from 1.01 Å for a 4‐residue loop to 1.94 Å for an 8‐residue loop. Three‐dimensional (3D) structures for several medium loops (20–30 residues) and for two large loops (54 and 61 residues) were predicted using residue–residue contact matrices divided into variable parts corresponding to the loops, and into a constant part corresponding to the known core of the protein. For each medium loop, a very limited number of sterically reasonable Cα traces (from 1 to 3) was found; RMSD values ranged from 2.4 to 5.9 Å. Single Cα traces predicted for each of the large loops possessed RMSD values of 4.5 Å. Generally, ab initio loop modeling presented in this work combines elements of computational procedures developed both for protein folding and for peptide conformational analysis. © 2001 John Wiley & Sons, Inc. Biopolymers (Pept Sci) 60: 153–168, 2001

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.

A systematic molecular mechanics study of the alamethicin molecule was made to determine a set of low-energy conformers in vacuo and in aqueous environment. The behavior of these conformers was investigated at the phase boundary which was modeled as a plane dividing two compartments with solvation properties of water and octanol with a constant electric field applied normal to the boundary. The calculations were performed with a molecular mechanics program for calculation of stable conformations at the phase boundary utilizing the Empiric Conformational Energy Program for Peptides force field and the Hopfinger-Scheraga solvation model. 371 minimum energy conformers of alamethicin, determined in vacuo with the build-up procedure, were used as starting conformations for energy minimization in aqueous environment and at the phase boundary. Only 49 interphase-bound structures were within 12 kcal/mol of the minima which was found. No helical structures having values close to the canonical parameters for an alpha- or 3(10)-helix were found despite the presence of eight alpha-methylalanine residues which favor the formation of these helices; four helix-like structures were found, having all negative phi, psi values. All the helical conformers have very high energies in water (approximately 14 kcal/mol), but are quite stable at the phase boundary (3.7-6.8 kcal/mol above the lowest minima found). The implications of these results for proposed mechanisms for membrane-binding and voltage-dependent gating are considered.

The total semi‐empirical conformational analysis of the oxytocin molecule has been carried out. It has been revealed the two main types of stable structures of cyclic moiety backbone and the great lability of the tail. The optimal spacing of cyclic moiety side chains has been found for every backbone structure. The calculation results are in good agreement with the data of physico‐chemical investigations. Among the set of stable molecule structures reported in the present study are structures with β‐turn conformation of the cyclic moiety backbone and without closer spacing of the cyclic moiety and the tail, as well as structures with closely spaced N‐ and C‐terminal parts which, however, lack β‐turn in the cyclic moiety.

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