N-terminal and C-terminal heptad repeats (NHR and CHR) of HIV type I (HIV-1) glycoprotein 41 are known to be regions directly related to cell fusion during virus attack, and their complex core constructs a coiled-coil structure in the fusion process. In our recent studies, MT-4/17-3-6, a strain of HIV-1, showed the strong resistance to peptide fusion inhibitors compared with other strains such as MT-4/LAI, L-2 and CU98-26, and had a distinctive (LM)-M-565 mutation in the central region of NHR. To investigate the relationship between the mutation and resistance, we performed a molecular modeling of the coiled-coil of MT-4/17-3-6 by using energy minimization and molecular dynamics simulation based on the MT-4/LAI X-ray structure. As a result, we found that H 164 in the NHR was pushed to the outer side by this mutation, and three hydrogen bond bridges of y(638)-H-564-E-560-Q(650) could be formed, enclosing the coiled-coil. The binding of peptide inhibitors would be disturbed by the structural stabilization of these bridges in MT-4/17-3-6. (c) 2005 Elsevier Inc. All rights reserved.