Molecular dynamics study of the differences in the human defensin behavior near a modelled water/membrane interface

Abstract

O comportamento das defensinas humanas HNP-1, HNP-2 e HNP-3 é estudado em um modelo de interface H 2 O/CCl 4 por simulações de dinâmica molecular. O comportamento distinto do HNP-3, quando comparado ao dos HNP 1 e 2, pode ser associado ao fato de o HNP-3 ser a menos potente das três defensinas, uma vez que seus resíduos apolares, que poderiam atacar as membranas celulares dos organismos patogênicos estão protegidos no interior do peptídeo. Três mecanismos encontrados na literatura propõem que a ação dos HNPs sobre membranas ocorra, principalmente, pela interação entre os seus resíduos polares e os da superfície da membrana. Esses modelos não explicam com clareza o papel da região hidrofóbica da membrana na manutenção da estrutura quaternária do dímero de HNP, quando em contato com o interior da membrana. O conhecimento do comportamento da estrutura dimérica no estágio inicial da penetração na membrana, considerando, principalmente, a natureza hidrofóbica dos HNPs, mostrou-se essencial para explicar as diferenças nas suas ações. Este trabalho contribui para o entendimento do mecanismo da ação antimicrobiana das defensinas.Human defensins HNP-1, HNP-2 and HNP-3 behavior is studied in a membrane interface model H 2 O/CCl 4 by molecular dynamics simulation. The distinct HNP-3 behavior, when compared to HNP 1 and 2, can be associated to the fact that HNP-3 is the least potent of the three defensins, since its apolar residues, which could attack the cellular membranes of the pathogenic organisms, are shielded in the inner region of the peptide. Three mechanisms were proposed to explain the HNP action on cellular membranes. These mechanisms are unable to enlighten the membrane hydrophobic part role for preserving the quaternary structure of the peptide when it is interacting with the inner part of the membrane. They suggest that the damaging is mainly caused by the interactions between the localized charges of the peptides with charges on the membrane surface. These models do not clearly explain what the hydrophobic region role is in the stabilization of the quaternary HNP structure, when it is interacting with a membrane. The understanding of how the HNP dimers structure is conserved at the first stages of the insertion into the membrane is fundamental to explain the different activities of the peptides. This work aims at contributing for the understanding of the mechanism of the defensins antimicrobial action.

Study of the Interaction of Human Defensins with Cell Membrane Models: Relationships between Structure and Biological Activity

“…The rmsd data presented in Table for the HNP backbones show that deviation from the initial structure oscillates around 2.3 Å for HNP-1 and HNP-3 and 3.8 Å for HNP-2. These 2.3 Å deviations are not sufficiently significant to change the tertiary or quaternary structures, as already shown by MD simulation of the HNPs in aqueous solution and interface, thus indicating that the structures of these HNPs in this interface also are maintained. Under these conditions, the HNP-1 and HNP-3 dimers maintain the shape of a basket partially flattened on the top, according to the structures determined by crystallography and in aqueous solution by NMR and MD. , In the case of HNP-2, the highest rmsd among HNPs (∼3.8 Å) indicates a more flattening on the top of the structure.…”

“…The rmsd data presented in Table 1 for the HNP backbones show that deviation from the initial structure oscillates around 2.3 Å for HNP-1 and HNP-3 and 3.8 Å for HNP-2. These 2.3 Å deviations are not sufficiently significant to change the tertiary or quaternary structures, as already shown by MD simulation of the HNPs in aqueous solution 45 and interface, 46 thus indicating that the structures of these HNPs in this interface also are maintained. Under these conditions, the HNP-1 and HNP-3 dimers maintain the shape of a basket partially flattened on the top, according to the structures determined by crystallography and in aqueous solution by NMR and MD.…”

“…These HBs formed between amine and carbonyl groups (N-H‚‚‚OdC) can also stabilize the dimeric structure that is in contact with the aqueous solution. This kind of stabilization, already described by Namba and co-workers, 45,46 occurs because some hydrophobic residues in the neighborhood maintain the solvent apart from the polar groups.…”