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 aug 2022
Accepted
13 okt 2022
First published
19 okt 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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