Issue 46, 2022

Partial peptide dissociation and binding groove plasticity in two major histocompatibility complex class I alleles – differences between alleles versus force field and sampling effects

Abstract

Major histocompatibility complex class I (MHC I) reports a cell's health status by presenting antigenic peptides inside its binding groove. However, MHC I binding grooves can differ largely in their plasticity, from binding grooves that are conformationally stable by themselves to those that require a high-affinity peptide to be bound to attain conformational stability. These latter MHC I alleles are dependent on the C-terminus of the peptide that stabilizes the F-pocket region of their binding grooves. It has remained unclear to what extent a peptide-MHC I complex (pMHC I) can tolerate the (intermittent) partial dissociation of high-affinity peptides, especially of the peptide's N-terminus. Using bias exchange umbrella sampling (BEUS), a technique to achieve enhanced sampling in molecular dynamics (MD) simulations, we obtained the free-energy profiles of the N-terminal dissociation of a respective high-affinity peptide from HLA-B*35:01 and HLA-B*44:02, two alleles on opposite ends of the scale regarding binding groove plasticity. The potential of mean force (PMF) for HLA-B*35:01 was calculated for two different sets of starting structures and is compared with a PMF obtained previously with a different force field to disentangle allele differences from force field and sampling effects. For both alleles, the free-energy profiles indicate that the peptide N-terminus dissociates in a substantial fraction of the pMHC I, suggesting that their crystal structures with fully bound peptides only partially capture the dynamic conformational ensemble of pMHC I in solution, and thus in the cell.

Graphical abstract: Partial peptide dissociation and binding groove plasticity in two major histocompatibility complex class I alleles – differences between alleles versus force field and sampling effects

Supplementary files

Article information

Article type
Paper
Submitted
25 8 2022
Accepted
13 10 2022
First published
19 10 2022
This article is Open Access
Creative Commons BY-NC license

RSC Adv., 2022,12, 29908-29914

Partial peptide dissociation and binding groove plasticity in two major histocompatibility complex class I alleles – differences between alleles versus force field and sampling effects

S. Wingbermühle and L. V. Schäfer, RSC Adv., 2022, 12, 29908 DOI: 10.1039/D2RA05324A

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