Molecular Dynamics Simulations to Provide Insights into Epitopes Coupled to the Soluble and Membrane-Bound MHC-II Complexes

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Date: Aug. 19, 2013
From: PLoS ONE(Vol. 8, Issue 8)
Publisher: Public Library of Science
Document Type: Article
Length: 7,539 words
Lexile Measure: 1600L

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Author(s): Martiniano Bello *, Jose Correa-Basurto


Major histocompatibility complex (MHC) molecules are heterodimeric proteins that bind antigenic peptides as part of the adaptive immune response to foreign pathogens. MHC class I (MHC-I) presents primarily peptides of endogenous origin, whereas MHC class II (MHC-II) binds molecules derived from exogenous proteins. These exogenous molecules are commonly short peptides, the products of the degradation process for exogenous proteins. After a peptide binds to a MHC-II molecule to create a pMHC-II complex, the peptide is presented to T-cell receptors (TCRs), which identify foreign antigens [1]. Unlike MHC-I, whose peptide-binding groove is geometrically optimized to bind small peptides smaller than 11 residues in length, MHC-II has a binding groove that is open at both ends, thus allowing peptides of varying lengths (12 to 26) to bind [2]-[4]. Only a core of nine consecutive residues interacts with the MHC-II molecule at certain anchor residues [5]. Furthermore, this peptide core can be flanked by a variable number of residues [4], which could enhance the processing of epitopes and modulate the activation of T cells after reaching the TCR [6].

X-ray studies have provided some evidence of the rules that govern peptide recognition by MHC-II. First, despite the lack of significant structural variation among the crystallographic structures of peptide-free MHC-II and pMHC-II forms, alternate conformations have been reported for both MHC-II states [7]-[12]. In fact, an increase in the hydrodynamic radius and a decrease in helicity have been observed for the peptide-free form of MHC-II (DRB1*0101) with respect to pMHC-II [12], [13]. Interestingly, the opposite behavior occurs upon peptide binding, suggesting that there is higher conformational mobility for the peptide-free MHC-II form. Second, the peptide in the peptide-binding groove adopts a type II polyproline helix, which causes the peptide to twist in a specific manner, with the sequestration of the peptide side chains in the polymorphic pockets (Ps) of the MHC-II molecule [14], [15]. Generally, these Ps accommodate the side chains of peptide residues and can be divided into two classes: the class comprising P1, P4, P6, and P9, which have been identified as major anchors and are localized in solvent-inaccessible regions, and the class comprising P2, P3, P7, and P10, which are smaller pockets that function as auxiliary anchors [16], [17]. This type of molecular recognition has been interpreted as a docking event stabilized by a series of sequential and independent interactions formed between residues of the peptide and Ps [18].

With respect to the conformational behavior of MHCs in aqueous environments, most MD simulations performed with MHC molecules have been focused on MHC-I [19]-[21]. Based on these studies, we know that MHC-I experiences a reduction in conformational mobility upon pMHC-I complex formation [22]; however, such studies took into consideration only the peptide-binding groove (chains [alpha] and [beta]) and not the whole MHC-I molecule. Later, Wan et al. showed that MD simulations that do not take into account the entire complex (light and heavy [alpha] and [beta] chains) could give misleading results for the conformational mobility...

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Gale Document Number: GALE|A478215333