A ′Fragment Fitting Approach′ to Model Disulfide Loops by Utilizing Homologous Peptide Fragments from Unrelated Proteins of Known Structures: Application to the V3 Loop of the HIV-1 Envelope Glycoprotein gp120

Abstract

The V3 loop of the human immunodeficiency virus type 1 (HIV-1) envelope glycoprotein gp120 has gained considerable attention for develo** subunit vaccines against HIV-1 and also as a target to develop anti-HIV-1 drugs. These endeavors would be significantly enhanced by understanding the structural aspects of this loop. The structure of the full-length V3 loop has not been defined yet. Therefore, a novel modeling technique, termed `Fragment Fitting Approach′ (FFA), was developed to model the V3 loop. This technique utilizes fragments (³ 6 residue long) with local sequence and secondary structure similarity from unrelated proteins with known x-ray crystallographic structure and concatenating the fragments to build the model. A systematic search method was devised to identify the fragments using the combined criteria of sequence and secondary structure identity and/or similarity, predicted by a combination of methods. FFA requires partial three-dimensional coordinates of the target sequence to be modelled to get the overall coordinate path correct. The method was validated with nine disulfide-bonded loops from the Protein data bank. The modelled structures conform well with the corresponding x-ray crystallographic structures. As the models were built using the x-ray coordinates with reasonable resolution (£ 3 Å), they are expected to have stereochemically correct structures. The modelled V3 loop structure might assist in structure-based drug design of anti-HIV-1 agents targeted to this loop.