Antigen presentation by major histocompatibility complex (MHC) proteins is essential for adaptive immunity. Prior to presentation, peptides need to be generated from proteins that are either produced by the cell’s own translational machinery or that are funneled into the endo-lysosomal vesicular system. The prolonged interaction between a T cell receptor and specific pMHC complexes, after an extensive search process in secondary lymphatic organs, eventually triggers T cells to proliferate and to mount a specific cellular immune response. Once processed, the peptide repertoire presented by MHC proteins largely depends on structural features of the binding groove of each particular MHC allelic variant. Additionally, two peptide editors—tapasin for class I and HLA-DM for class II—contribute to the shaping of the presented peptidome by favoring the binding of high-affinity antigens. Although there is a vast amount of biochemical and structural information, the mechanism of the catalyzed peptide exchange for MHC class I and class II proteins still remains controversial, and it is not well understood why certain MHC allelic variants are more susceptible to peptide editing than others. Recent studies predict a high impact of protein intermediate states on MHC allele-specific peptide presentation, which implies a profound influence of MHC dynamics on the phenomenon of immunodominance and the development of autoimmune diseases. Here, we review the recent literature that describe MHC class I and II dynamics from a theoretical and experimental point of view and we highlight the similarities between MHC class I and class II dynamics despite the distinct functions they fulfill in adaptive immunity.

Understanding and control of structures and rates involved in protein ligand binding are essential for drug design. Unfortunately, atomistic molecular dynamics (MD) simulations cannot directly sample the excessively long residence and rearrangement times of tightly binding complexes. Here we exploit the recently developed multi-ensemble Markov model framework to compute full protein-peptide kinetics of the oncoprotein fragment 25–109Mdm2 and the nano-molar inhibitor peptide PMI. Using this system, we report, for the first time, direct estimates of kinetics beyond the seconds timescale using simulations of an all-atom MD model, with high accuracy and precision. These results only require explicit simulations on the sub-milliseconds timescale and are tested against existing mutagenesis data and our own experimental measurements of the dissociation and association rates. The full kinetic model reveals an overall downhill but rugged binding funnel with multiple pathways. The overall strong binding arises from a variety of conformations with different hydrophobic contact surfaces that interconvert on the milliseconds timescale.

The intracellular trafficking of major histocompatibility complex class I (MHC-I) proteins is directed by three quality control mechanisms that test for their structural integrity, which is correlated to the binding of high-affinity antigenic peptide ligands. To investigate which molecular features of MHC-I these quality control mechanisms detect, we have followed the hypothesis that suboptimally loaded MHC-I molecules are characterized by their conformational mobility in the F-pocket region of the peptide-binding site. We have created a novel variant of an MHC-I protein, K b -Y84C, in which two a-helices in this region are linked by a disulfide bond that mimics the conformational and dynamic effects of bound highaffinity peptide. K b -Y84C shows a remarkable increase in the binding affinity to its light chain, beta-2 microglobulin (b 2 m), and bypasses all three cellular quality control steps. Our data demonstrate (1) that coupling between peptide and b 2 m binding to the MHC-I heavy chain is mediated by conformational dynamics; (2) that the folded conformation of MHC-I, supported by b 2 m, plays a decisive role in passing the ER-to-cell-surface transport quality controls; and (3) that b 2 m association is also tested by the cell surface quality control that leads to MHC-I endocytosis.

The human MHC class I protein HLA-B*27:05 is statistically associated with ankylosing spondylitis, unlike HLA-B*27:09, which differs in a single amino acid in the F pocket of the peptide-binding groove. To understand how this unique amino acid difference leads to a different behavior of the proteins in the cell, we have investigated the conformational stability of both proteins using a combination of in silico and experimental approaches. Here, we show that the binding site of B*27:05 is conformationally disordered in the absence of peptide due to a charge repulsion at the bottom of the F pocket. In agreement with this, B*27:05 requires the chaperone protein tapasin to a greater extent than the conformationally stable B*27:09 in order to remain structured and to bind peptide. Taken together, our data demonstrate a method to predict tapasin dependence and physiological behavior from the sequence and crystal structure of a particular class I allotype.Keywords: Ankylosing spondylitis r HLA-B27 r Major histocompatibility complex r Molecular dynamics r Natively unstructured proteins r Protein folding r Simulations Additional supporting information may be found in the online version of this article at the publisher's web-site Introduction MHC class I molecules are heterotrimeric proteins that transport antigenic peptides to the cell surface and present them to cytotoxic T cells. They consist of the transmembrane heavy chain (HC), the noncovalently associated light chain beta-2 microglobulin (β 2 m), and an antigenic peptide of eight to ten amino acids. The Correspondence: Prof. Sebastian Springer e-mail: s.springer@jacobs-university.de extracellular part of the heavy chain comprises the α 1 , α 2 , and α 3 domains. The α 1 and α 2 domains form the peptide-binding groove, a superdomain that consists of an antiparallel beta sheet surmounted by two alpha helices, between which the peptide binds [1,2].In the cell, peptide binding to class I is a multistep process within the ER. It involves the peptide-loading complex, which consists of the peptide transporter associated with antigen processing (TAP) that transports peptides from the cytosol into the ER lumen [3] and several chaperone proteins such as tapasin, which binds both to the class I molecule and TAP [4,5].C 2015 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim www.eji-journal.eu Eur. J. Immunol. 2015. 45: 1248-1257 Molecular immunology 1249The sequence of peptides that can bind to class I is determined by interactions with the amino acid side chains of the peptide-binding groove. The high sequence polymorphism of the peptide-binding groove in human class I molecules (human leukocyte antigens, HLA-A, -B, and -C) means that different allotypes bind different peptides; thus, individual HLA allotypes-such as HLA-B27-support-specific immune responses and are statistically associated with disease [6,7]. Among the subtypes of HLA-B27 [8,9], HLA-B*27:05 (B*27:05) shows a very strong statistical association with spondyloarthropathies such as ankylosing spondylitis (AS), in contr...