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Molecular dynamics simulations to provide insights into epitopes coupled to the soluble and membrane-bound MHC-II complexes.

ABSTRACT: Epitope recognition by major histocompatibility complex II (MHC-II) is essential for the activation of immunological responses to infectious diseases. Several studies have demonstrated that this molecular event takes place in the MHC-II peptide-binding groove constituted by the ? and ? light chains of the heterodimer. This MHC-II peptide-binding groove has several pockets (P1-P11) involved in peptide recognition and complex stabilization that have been probed through crystallographic experiments and in silico calculations. However, most of these theoretical calculations have been performed without taking into consideration the heavy chains, which could generate misleading information about conformational mobility both in water and in the membrane environment. Therefore, in absence of structural information about the difference in the conformational changes between the peptide-free and peptide-bound states (pMHC-II) when the system is soluble in an aqueous environment or non-covalently bound to a cell membrane, as the physiological environment for MHC-II is. In this study, we explored the mechanistic basis of these MHC-II components using molecular dynamics (MD) simulations in which MHC-II was previously co-crystallized with a small epitope (P7) or coupled by docking procedures to a large (P22) epitope. These MD simulations were performed at 310 K over 100 ns for the water-soluble (MHC-IIw, MHC-II-P(7w), and MHC-II-P(22w)) and 150 ns for the membrane-bound species (MHC-IIm, MHC-II-P(7m), and MHC-II-P(22m)). Our results reveal that despite the different epitope sizes and MD simulation environments, both peptides are stabilized primarily by residues lining P1, P4, and P6-7, and similar noncovalent intermolecular energies were observed for the soluble and membrane-bound complexes. However, there were remarkably differences in the conformational mobility and intramolecular energies upon complex formation, causing some differences with respect to how the two peptides are stabilized in the peptide-binding groove.

SUBMITTER: Bello M

PROVIDER: S-EPMC3747130 | biostudies-literature | 2013

REPOSITORIES: biostudies-literature

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Molecular dynamics simulations to provide insights into epitopes coupled to the soluble and membrane-bound MHC-II complexes.

Bello Martiniano M Correa-Basurto Jose J

PloS one 20130819 8

Epitope recognition by major histocompatibility complex II (MHC-II) is essential for the activation of immunological responses to infectious diseases. Several studies have demonstrated that this molecular event takes place in the MHC-II peptide-binding groove constituted by the α and β light chains of the heterodimer. This MHC-II peptide-binding groove has several pockets (P1-P11) involved in peptide recognition and complex stabilization that have been probed through crystallographic experiments ...[more]

PMID: 23977319

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Project description:There is growing interest in models of regulatory sequence evolution. However, existing models specifically designed for regulatory sequences consider the independent evolution of individual transcription factor (TF)-binding sites, ignoring that the function and evolution of a binding site depends on its context, typically the cis-regulatory module (CRM) in which the site is located. Moreover, existing models do not account for the gene-specific roles of TF-binding sites, primarily because their roles often are not well understood. We introduce two models of regulatory sequence evolution that address some of the shortcomings of existing models and implement simulation frameworks based on them. One model simulates the evolution of an individual binding site in the context of a CRM, while the other evolves an entire CRM. Both models use a state-of-the art sequence-to-expression model to predict the effects of mutations on the regulatory output of the CRM and determine the strength of selection. We use the new framework to simulate the evolution of TF-binding sites in 37 well-studied CRMs belonging to the anterior-posterior patterning system in Drosophila embryos. We show that these simulations provide accurate fits to evolutionary data from 12 Drosophila genomes, which includes statistics of binding site conservation on relatively short evolutionary scales and site loss across larger divergence times. The new framework allows us, for the first time, to test hypotheses regarding the underlying cis-regulatory code by directly comparing the evolutionary implications of the hypothesis with the observed evolutionary dynamics of binding sites. Using this capability, we find that explicitly modeling self-cooperative DNA binding by the TF Caudal (CAD) provides significantly better fits than an otherwise identical evolutionary simulation that lacks this mechanistic aspect. This hypothesis is further supported by a statistical analysis of the distribution of intersite spacing between adjacent CAD sites. Experimental tests confirm direct homodimeric interaction between CAD molecules as well as self-cooperative DNA binding by CAD. We note that computational modeling of the D. melanogaster CRMs alone did not yield significant evidence to support CAD self-cooperativity. We thus demonstrate how specific mechanistic details encoded in CRMs can be revealed by modeling their evolution and fitting such models to multispecies data.

Dataset Information

Molecular dynamics simulations to provide insights into epitopes coupled to the soluble and membrane-bound MHC-II complexes.

Publications

Molecular dynamics simulations to provide insights into epitopes coupled to the soluble and membrane-bound MHC-II complexes.

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