A molecular dynamics study of human defensins HBD-1 and HNP-3 in water

Mammalian defensins are crucial components of the innate immune system. They are characterized by three disulfide bridges and exhibit broad spectrum antibacterial activity. The spacing between the cysteines and disulfide connectivities in the two classes of defensins, the α- and β-forms, are different. The structural motif of 3 β-strands appears to be conserved in α- and β-defensins despite differences in disulfide connectivities and spacing between cysteines. In this study, Molecular Dynamics Simulations (MDS) have been carried out to study the conformational behavior of α- and β-defensins with and without disulfide bridges. Our results indicate that β-strands in the C-terminal region of HBD-1 and HNP-3 do not unfold during the course of MDS. The segment adopting a-helix in HBD-1 unfolds early during the simulations. The backbone hydrogen bonds in HBD-1 and HNP-3 are broken during MDS. When the disulfide bonds are absent, the N-terminal β-strand unfolds by 20 ns but β-strands are observed in the C-terminal region of HNP-3. HBD-1, without disulfide bridges, unfolds to a greater extent during the course of the MDS. Examination of distances between sulfur atoms of cysteines without disulfide bridges during the simulations indicate that there is no specific preference for native disulfide bridges, which could be the reason for the experimental observation of non-native disulfide bridge formation during chemical synthesis of human α- and β-defensins. Since defensins with non-native disulfide bridges are biologically active, the exact three dimensional structures observed for native HBD-1 and HNP-3 does not appear to be essential for exhibiting antibacterial activity

Amphipathic α-helices in proteins: results from analysis of protein structures

Amphipathic α-helices play a crucial role in mediating the interaction of peptides and proteins with membranes. We have analyzed protein structures for the occurrence of 18-residue amphipathic helices. We find several of these α-helices having average hydrophobic moments and average hydrophobicities that would favor their interaction with membranes. We have analyzed the distribution of net charge, helix length, normalized frequency of occurrence, and propensities of the 20 amino acids in the delineated 18-residue helices. We have observed distinct differences in the frequencies of occurrence of polar and hydrophobic amino acids at positions 1-18 in amphipathic and nonamphipathic helices. There are also differences in propensities of the 20 amino acids to occur at positions 1-18 of amphipathic and nonamphipathic helices. Synthetic peptides corresponding to some of these surface-seeking helices do possess antibacterial and/or hemolytic activities. Knowledge of the distribution of charges in 18-residue surface-seeking amphipathic α-helices, as well as propensity of occurrence of amino acids at various positions, would be useful inputs in the de novo design of amphipathic peptides

On the intrinsic propensity of the Asn-Gly sequence to fold into type I′ β-turn: molecular dynamics simulations of Asn-Gly β-turn containing peptide sequences

On the intrinsic propensity of the Asn-Gly sequence to fold into type I′ β-turn: molecular dynamics simulations of Asn-Gly β-turn containing peptide sequence