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1.
J Comput Aided Mol Des ; 24(12): 1035-51, 2010 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-20936494

RESUMO

Knowledge of the 3D structure of the binding groove of major histocompatibility (MHC) molecules, which play a central role in the immune response, is crucial to shed light into the details of peptide recognition and polymorphism. This work reports molecular modeling studies aimed at providing 3D models for two class I and two class II MHC alleles from Salmo salar (Sasa), as the lack of experimental structures of fish MHC molecules represents a serious limitation to understand the specific preferences for peptide binding. The reliability of the structural models built up using bioinformatic tools was explored by means of molecular dynamics simulations of their complexes with representative peptides, and the energetics of the MHC-peptide interaction was determined by combining molecular mechanics interaction energies and implicit continuum solvation calculations. The structural models revealed the occurrence of notable differences in the nature of residues at specific positions in the binding groove not only between human and Sasa MHC proteins, but also between different Sasa alleles. Those differences lead to distinct trends in the structural features that mediate the binding of peptides to both class I and II MHC molecules, which are qualitatively reflected in the relative binding affinities. Overall, the structural models presented here are a valuable starting point to explore the interactions between MHC receptors and pathogen-specific interactions and to design vaccines against viral pathogens.


Assuntos
Epitopos/química , Complexo Principal de Histocompatibilidade/imunologia , Simulação de Dinâmica Molecular , Peptídeos/química , Salmo salar/imunologia , Alelos , Sequência de Aminoácidos , Animais , Sítios de Ligação , Epitopos/imunologia , Epitopos/metabolismo , Humanos , Peptídeos/imunologia , Ligação Proteica/imunologia , Homologia de Sequência de Aminoácidos
2.
Methods Enzymol ; 437: 477-98, 2008.
Artigo em Inglês | MEDLINE | ID: mdl-18433643

RESUMO

This chapter reviews the application of classical and quantum-mechanical atomistic simulation tools used in the investigation of several relevant issues in nitric oxide reactivity with globins and presents different simulation strategies based on classical force fields: standard molecular dynamics, essential dynamics, umbrella sampling, multiple steering molecular dynamics, and a novel technique for exploring the protein energy landscape. It also presents hybrid quantum-classical schemes as a tool to obtain relevant information regarding binding energies and chemical reactivity of globins. As illustrative examples, investigations of the structural flexibility, ligand migration profiles, oxygen affinity, and reactivity toward nitric oxide of truncated hemoglobin N of Mycobacterium tuberculosis are presented.


Assuntos
Simulação por Computador , Globinas/química , Globinas/metabolismo , Óxido Nítrico/química , Óxido Nítrico/metabolismo , Fenômenos Biomecânicos , Metabolismo Energético , Heme/química , Inativação Metabólica , Cinética , Modelos Moleculares , Modelos Teóricos , Mycobacterium tuberculosis , Mioglobina/química , Mioglobina/metabolismo , Óxido Nítrico/farmacocinética , Oxigênio/metabolismo , Oxigênio/farmacologia , Ligação Proteica , Dobramento de Proteína , Teoria Quântica , Transdução de Sinais , Especificidade por Substrato , Hemoglobinas Truncadas/química
3.
J Am Chem Soc ; 130(5): 1688-93, 2008 Feb 06.
Artigo em Inglês | MEDLINE | ID: mdl-18189394

RESUMO

The capability of Mycobacterium tuberculosis to rest in latency in the infected organism appears to be related to the disposal of detoxification mechanisms, which converts the nitric oxide (NO) produced by macrophages during the initial growth infection stage into a nitrate anion. Such a reaction appears to be associated with the truncated hemoglobin N (trHbN). Even though previous experimental and theoretical studies have examined the pathways used by NO and O2 to access the heme cavity, the eggression pathway of the nitrate anion is still a challenging question. In this work we present results obtained by means of classical and quantum chemistry simulations that show that trHbN is able to release rapidly the nitrate anion using an eggression pathway other than those used for the entry of both O2 and NO and that its release is promoted by hydration of the heme cavity. These results provide a detailed understanding of the molecular basis of the NO detoxification mechanism used by trHbN to guarantee an efficient NO detoxification and thus warrant survival of the microorganism under stress conditions.


Assuntos
Hemoglobinas Anormais/química , Hemoglobinas Anormais/metabolismo , Mycobacterium tuberculosis/química , Mycobacterium tuberculosis/metabolismo , Óxido Nítrico/metabolismo , Óxido Nítrico/toxicidade , Ânions/química , Sítios de Ligação , Simulação por Computador , Ligantes , Modelos Moleculares , Mycobacterium tuberculosis/efeitos dos fármacos , Nitratos/química , Nitratos/metabolismo , Ligação Proteica , Estrutura Terciária de Proteína , Água/química , Água/metabolismo
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