Partial Dissociation of Truncated Peptides Influences the Structural Dynamics of the MHCI Binding Groove

Abstract

Antigen processing on MHCI involves the exchange of low-affinity peptides by high-affinity, immunodominant ones. This peptide editing process is mediated by tapasin and ERAAP at the peptide C- and N-terminus, respectively. Since tapasin does not contact the peptide directly, a sensing mechanism involving conformational changes likely allows tapasin to distinguish antigen-loaded MHCI molecules from those occupied by weakly bound, non-specific peptides. To understand this mechanism at the atomic level, we performed molecular dynamics simulations of MHCI allele B*44:02 loaded with peptides truncated or modified at the C- or N-terminus. We show that the deletion of peptide anchor residues leads to reversible, partial dissociation of the peptide from MHCI on the microsecond timescale. Fluctuations in the MHCI α2−1 helix segment, bordering the binding groove and cradled by tapasin in the PLC, are influenced by the peptide C-terminus occupying the nearby F-pocket. Simulations of tapasin complexed with MHCI bound to a low-affinity peptide show that tapasin widens the MHCI binding groove near the peptide C-terminus and weakens the attractive forces between MHCI and the peptide. Our simulations thus provide a detailed, spatially resolved picture of MHCI plasticity, revealing how peptide loading status can affect key structural regions contacting tapasin.

The partial dissociation of MHC class I–bound peptides exposes their N terminus to trimming by endoplasmic reticulum aminopeptidase 1

“…Partial peptide dissociations have been observed previously in MD studies of HLA-B*27:05 ( 40 ), HLA-A*02:01 ( 41 ), as well as in MD simulations of the HLA-B*44:02 loaded with peptides truncated or modified at the C or N terminus ( 42 ). In addition, a “flapping” behavior of both the N- and C-terminal regions of the peptides has been reported in a large-scale MD study of HLA-B*08:01 in complex with 172 variants (single-point mutants) of the Epstein-Barr virus peptide FLRGRAYGL ( 43 ).…”

Peptide and Peptide-Dependent Motions in MHC Proteins: Immunological Implications and Biophysical Underpinnings

“…With ever-growing improvements in computer hardware, MD simulations have advanced considerably, such that we are now seeing simulations of entire protein folding reactions on timescales extending beyond microseconds ( 32 ). MD simulations have been used extensively to study the motions of peptides bound to MHC-I proteins ( 15 , 33 – 51 ), as reviewed recently by Freund and colleagues ( 52 ). MD simulations have the advantage of tracking actual motion in atomic detail, capturing different conformations as a function of time.…”

Sequence-structure-function relationships in class I MHC: a local frustration perspective

“…For many alleles, A, B and F pockets are decisive for peptide binding (A/B and F pockets binding N- and C-terminus of peptide ligands, respectively). Structural integrity of the F pocket of some alleles was previously shown to be more sensitive to peptide truncation in MD simulations than those of A and B pockets [41,94–96]. This implies that contacts between peptide C-terminus and HLA F pocket are highly important for molecular stability.…”

“…Only certain allele groups containing specific epitopes interact with KIR [25,37]. Structural details of the PLC-pMHC interaction were also only recently revealed [34,38–41].…”