Estudo da estrutura e da solvatação do HNP-3, um antibiótico natural, por dinâmica molecular

Namba, Adriana M.; Degrève, Léo

doi:10.1590/s0100-40422004000100006

Cited by 4 publications

(5 citation statements)

References 14 publications

(19 reference statements)

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“…The aim of this paper is to identify how the membrane hydrophobic region helps to conserve the HNP dimer stability, identifying in this way the main factors that provide the distinct antimicrobial activities of the dimeric forms of the human defensins HNP-1, HNP-2 and HNP-3 in a membrane interface model. The present studies extend previous analyses about the structure and hydration of the HNP-3 developed, 33,34 showing a high solvent …”

Section: Introductionsupporting

confidence: 89%

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

Namba¹,

Lourenzoni²,

Degrève³

2007

J. Braz. Chem. Soc.

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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.

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Section: Introductionsupporting

confidence: 89%

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

Namba¹,

Lourenzoni²,

Degrève³

2007

J. Braz. Chem. Soc.

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“…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.…”

Section: Resultsmentioning

confidence: 49%

“…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 high rigidity of the monomers structures is explained by the presence of the three disulfide bonds, which had been previously characterized by nuclear magnetic resonance (NMR), , circular dichroism (CD), and fluorescence spectroscopy measurements .…”

Section: Resultsmentioning

confidence: 49%

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

et al. 2007

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The HNP-1, HNP-2, and HNP-3 defensins are human antimicrobial peptides produced in response to microbial invasion. Their properties are distinct, with a more potent action for HNP-3. In this study, the relationship between their structural dissimilarities and their different microbial actions was evaluated by molecular dynamics simulation. Structural determinants related to their intra- and intermolecular interactions were defined for each HNP using a simplified membrane model consisting of a water/n-hexane interface. The hydrophobic portion of the HNPs promotes their diffusion to the interface with a concomitant, slight change in the structure induced by the intermolecular electrostatic interactions between the HPN molecules and the interface. As a consequence, different orientations are probably adopted by the HNPs at the interface, which may explain their different actions. The interaction of HNP-1 and HNP-2 with the surfaces was also studied using Langmuir monolayers as a biomimetic system. It was found that peptides adsorb rapidly at n-hexane/water interfaces as well as at phospholipid Langmuir monolayers but not at the air/liquid interface. This reveals that the presence of an organic phase is required for the exposure of the hydrophobic groups of the peptides. In addition, adsorption kinetics and surface pressure-area isotherms for Langmuir monolayers suggested that the lipid-peptide interaction is strongly influenced by the monolayer electrical charge and packing, depending also on the HPN structure. This study supports a model in which defensins, acting in a dimeric form, are able to disrupt membranes. The model also shows that the individual structures of the HNPs are responsible for their different actions on microbes.

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“…It is generally accepted that the protein‐solvent interactions play a major role in protein folding, and that the hydration structure is mediated by means of the hydrogen bonds that cover the proteins surfaces [21, 22]. Furthermore, molecular simulations studies have enlightened the complex solvent‐dependent processes [23–25] such as the helix‐coil transitions [26] in peptides and the formation of β‐hairpins [27] so that they may be able to contribute in the precise determination of the hydrophobicity of the amino acids as well. The quantitative evaluation of the magnitude of the hydrophobic contributions of the amino acid side chains in the native structure of the proteins remains to be elucidated in protein sciences [13].…”

Section: Background Theory and Prelaboratory Preparationmentioning

confidence: 99%

Use of molecular dynamics data in biochemistry courses

Mazzé

Fuzo

Degrève

et al. 2008

Biochem Molecular Bio Educ

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The aim of this manuscript is to explain the application of an amphipathy scale obtained from molecular dynamics simulations and to demonstrate how it can be useful in the protein structure field. It is shown that this scale is easy to be used with the advantage of revealing domains of transmembrane a-helix of proteins without the need of knowing anything besides the protein primary structure. In addition, it allows the students to correlate concepts of protein structure and function, energy minimization, molecular dynamics simulations, and protein location.

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Estudo da estrutura e da solvatação do HNP-3, um antibiótico natural, por dinâmica molecular

Cited by 4 publications

References 14 publications

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

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

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

Use of molecular dynamics data in biochemistry courses

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