Flexibility of the MHC class II peptide binding cleft in the bound, partially filled, and empty states: A molecular dynamics simulation study

Abstract

Major histocompatibility (MHC) Class II cell surface proteins present antigenic peptides to the immune system. Class II structures in complex with peptides but not in the absence of peptide are known. Comparative molecular dynamics (MD) simulations of a Class II protein (HLA‐DR3) with and without CLIP (invariant chain‐associated protein) peptide were performed starting from the CLIP‐bound crystal structure. Depending on the protonation of acidic residues in the P6 peptide‐binding pocket the simulations stayed overall close to the start structure. The simulations without CLIP showed larger conformational fluctuations especially of α‐helices flanking the binding cleft. Largest fluctuations without CLIP were observed in a helical segment near the peptide C‐terminus binding region matching a segment recognized by antibodies specific for empty Class II proteins. Simulations on a Val86Tyr mutation that fills the peptide N‐terminus binding P1 pocket or of a complex with a CLIP fragment (dipeptide) bound to P1 showed an unexpected long range effect. In both simulations the mobility not only of P1 but also of the entire binding cleft was reduced compared to simulations without CLIP. It correlates with the experimental finding that the CLIP fragment binding to P1 is sufficient to prevent antibody recognition specific for the empty form at a site distant from P1. The results suggest a mechanism how a local binding event of small peptides or of an exchange factor near P1 may promote peptide binding and exchange through a long range stabilization of the whole binding cleft in a receptive (near bound) conformation. © 2008 Wiley Periodicals, Inc. Biopolymers 91: 14–27, 2009.This article was originally published online as an accepted preprint. The “Published Online” date corresponds to the preprint version. You can request a copy of the preprint by emailing the Biopolymers editorial office at biopolymers@wiley.com

F pocket flexibility influences the tapasin dependence of two differentially disease‐associated MHC Class I proteins

“…For each region, we then measured how the distance of the centers of mass varied during the simulation. In both subtypes, the peptide-bound binding groove showed the lowest width variation, similarly to published data [5,32]. Empty B*27:09 showed an intermediate width variation between that of the empty B*27:05 and peptide-bound complexes, especially in regions II and III, as We next hypothesized that if empty B*27:05 was indeed more conformationally disordered than empty B*27:09, it should expose a larger proportion of its F pocket to the solvent.…”

Conformational lability in the class II MHC 310helix and adjacent extended strand dictate HLA-DM susceptibility and peptide exchange

“…Several factors indicate that the conformation observed in the αF54C mutant can be adopted by the WT and is relevant to DMmediated peptide exchange. Modeling studies of MHC II suggest that the N-terminal side of the peptide binding site undergoes conformational alteration concurrent with peptide release (32)(33)(34). In a molecular dynamics simulation of peptide-free MHC II (32), we observed changes strikingly similar to those observed in the αF54C structure determined here, in particular, a change in pitch and partial unwinding of the 3 10 helix and concerted rotamer changes of αF51,αF45, αF48 and βF89 (SI Appendix, Fig.…”

“…6, orange). Computational studies suggest that the conformation of the peptide-free protein has alterations near the P1 pocket as well as elsewhere in the binding groove (32)(33)(34), with the α-subunit extended stand region occupying part of the canonical peptide binding site (32), creating a peptide refractive state. In the model shown in Fig.…”

Dynamic Influence of the Two Membrane-Proximal Immunoglobulin-Like Domains upon the Peptide-Binding Platform Domain in Class I and Class II Major Histocompatibility Complexes: Normal Mode Analysis

“…38) In class II MHC, some experimental and computational studies indicated that the introduction of a short peptide composed of two residues or G b86Y substitution to occupy only the "N-terminal side" pocket induced a significant stabilization of not only the pocket but also of the whole peptide-binding groove. 14,18,20) The other computational studies discussed the peptide-free form of class II MHC and demonstrated the flexibility of the "N-terminal side" pocket and its importance in peptide-binding over the other pockets. 16,19) Considering these circumstances, our results suggest that the membrane-proximal domains of class II MHC have a greater influence upon peptide-binding than those of class I MHC.…”

“…[1][2][3][4][5][6][7][8][9] Moreover, some experimental and theoretical studies of the peptide-free platform domain have received attention because its structure has not yet been crystallized in both classes. [10][11][12][13][14][15][16][17][18][19][20] On the other hand, the two membrane-proximal domains have attracted less interest than the platform domain. Some biochemical studies investigated the two membrane-proximal domains of class I MHC, suggesting the importance of b 2 m in peptide-binding.…”