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Variations in the electrostatic landscape of class II human leukocyte antigen molecule induced by modifications in the myelin basic protein peptide: a theoretical approach.

ABSTRACT: The receptor-ligand interactions involved in the formation of the complex between Class II Major Histocompatibility Complex molecules and antigenic peptides, which are essential for establishing an adaptive immunological response, were analyzed in the Class II Human Leukocyte Antigen (HLA)--Myelin Basic Protein (MBP) peptide complex (HLA-DRbeta1*1501-MBP) using a multipolar molecular electrostatic potential approach. The Human Leukocyte Antigen--peptide complex system was divided into four pockets together with their respective peptide fragment and the corresponding occupying amino acid was replaced by each of the remaining 19 amino acids. Partial atomic charges were calculated by a quantum chemistry approach at the Hatree Fock/3-21*G level, to study the behavior of monopole, dipole and quadrupole electrostatic multipolar moments. Two types of electrostatic behavior were distinguished in the pockets' amino acids: "anchoring" located in Pocket 1 and 4, and "recognition" located in Pocket 4 and 7. According to variations in the electrostatic landscape, pockets were ordered as: Pocket 1>Pocket 9>>Pocket 4 approximately Pocket 7 which is in agreement with the binding ability reported for Class II Major Histocompatibility Complex pockets. In the same way, amino acids occupying the polymorphic positions beta13R, beta26F, beta28D, beta9W, beta74A, beta47F and beta57D were shown to be key for this Receptor-Ligand interaction. The results show that the multipolar molecular electrostatic potential approach is appropriate for characterizing receptor-ligand interactions in the MHC-antigenic peptide complex, which could have potential implications for synthetic vaccine design.

SUBMITTER: Agudelo WA

PROVIDER: S-EPMC2613560 | biostudies-literature | 2009

REPOSITORIES: biostudies-literature

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Variations in the electrostatic landscape of class II human leukocyte antigen molecule induced by modifications in the myelin basic protein peptide: a theoretical approach.

Agudelo William A WA Galindo Johan F JF Ortiz Marysol M Villaveces José L JL Daza Edgar E EE Patarroyo Manuel E ME

PloS one 20090109 1

The receptor-ligand interactions involved in the formation of the complex between Class II Major Histocompatibility Complex molecules and antigenic peptides, which are essential for establishing an adaptive immunological response, were analyzed in the Class II Human Leukocyte Antigen (HLA)--Myelin Basic Protein (MBP) peptide complex (HLA-DRbeta1*1501-MBP) using a multipolar molecular electrostatic potential approach. The Human Leukocyte Antigen--peptide complex system was divided into four pocke ...[more]

PMID: 19132105

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Project description:Myelin basic protein (MBP) is an important component of the myelin sheath surrounding neurons, and it is directly affected in demyelinating diseases. MBP contains a relatively large number of post-translational modifications (PTMs), which have been reported to play a role in multiple sclerosis, while MBPs from lower vertebrates have been reported to be incapable of inducing multiple sclerosis or allergic encephalitis. This study reveals the extent of differences in PTM patterns for mammalian and nonmammalian MBPs. This included intact mass and de novo sequence analysis of approximately 85% of rattlesnake MBP, the first reptile MBP to be characterized, and of bovine MBP. We identified 12 PTMs at 11 sites in the five bovine MBP charge components, which include both previously reported and novel modifications. The most notable modification is an acetylation of lysine 121. Other modifications found in bovine MBP include N-terminal acetylation in components C1, C2, and C3; oxidation of methionine 19 in all five components; all charge isomers having both a mono- and dimethylated (symmetric) arginine at position 106; deimination in arginines 23 and 47 found only in component C8b; deimination of arginine 96 and deamidation in glutamine 102 found in components C2, C3, C8a, and C8b; phosphorylation in threonine 97 restricted to charge components C2 and C3; deimination in arginine 161 only found in component C3; deamidation of glutamine 120 was only observed in C3. All four deiminated arginines and one acetylated lysine were first experimentally revealed in this study for bovine MBP. Mascot database searching combined with de novo sequence analysis of rattlesnake MBP provided more than 85% sequence coverage. A few PTMs were also revealed in rattlesnake MBP: mono- and dimethylated Arg, protein N-terminal acetylation, and deiminated Arg. Overall, snake MBP was found to undergo less modification than bovine MBP on the basis of the mass heterogeneity of the intact protein, the bottom-up structure analysis, and the limited complexity of rattlesnake MBP chromatography. The combined data from this study and information from previous studies extend the known MBP PTMs, and PTMs unique to higher vertebrates are proposed.

Dataset Information

Variations in the electrostatic landscape of class II human leukocyte antigen molecule induced by modifications in the myelin basic protein peptide: a theoretical approach.

Publications

Variations in the electrostatic landscape of class II human leukocyte antigen molecule induced by modifications in the myelin basic protein peptide: a theoretical approach.

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