Molecular and structural determinants of adamantyl susceptibility to HLA-DRs allelic variants: an in silico approach to understand the mechanism of MLEs

Abstract

Class II major histocompatibility complex (MHC II) molecules as expressed by antigen-presenting cells are heterodimeric cell-surface glycoprotein receptors that are fundamental in initiating and propagating an immune response by presenting tumor-associated antigenic peptides to CD4(+)/T(H) cells. The loading efficiency of such peptides can be improved by small organic compounds (MHC Loading Enhancers-MLEs), that convert the non-receptive peptide conformation of MHC II to a peptide-receptive conformation. In a reversible reaction, these compounds open up the binding site of MHC II molecules by specific interactions with a yet undefined pocket. Here, we performed molecular docking and molecular dynamics simulation studies of adamantyl compounds on the predicted cavity around the P1 pocket of 2 allelic variants of HLA-DRs. The purpose was to investigate the suitability of adamantyl compounds as MLEs at the dimorphic β86 position. Docking studies revealed that besides numerous molecular interactions formed by the adamantyl compounds, Asnβ82, Tyrβ83, and Thrβ90 are the crucial amino acid residues that are characterized as the "sensors" of peptide loading. Molecular dynamics simulation studies exposed the dynamical structural changes that HLA-DRs adopted as a response to binding of 3-(1-adamantyl)-5-hydrazidocarbonyl-1H-pyrazole (AdCaPy). The conformations of AdCaPy complexed with the Glyβ86 HLA-DR allelic variant are well correlated with the stabilized form of peptide-loaded HLA-DRs, further confirming the role of AdCaPy as a MLE. Hydrogen bonding interaction analysis clearly demonstrated that after making suitable contacts with AdCaPy, HLA-DR changes its local conformation. However, AdCaPy complexed with HLA-DR having Valβ86 at the dimorphic position did not accommodate AdCaPy as MLE due to steric hindrance caused by the valine.

Inhibition of tyrosinase by 4H‐chromene analogs: Synthesis, kinetic studies, and computational analysis

“…Finally, Table summarizes the affinity energy values computed by the MVD program for the TYR‐inhibitor complexes. Despite, the MOLDOCK scoring function not describing the relationship between the in silico and experimental data sufficiently well, it was found that the computed values are suitable for qualitative analysis in the case when multiple orientations are observed for the same compound. It is important to clarify that in the present work, the interest was only focused on predicting the position of the analogs within the active site of tyrosinase.…”

In Silico and In Vitro Analysis of Interaction between Ximelagatran and Human Leukocyte Antigen (HLA)-DRB1*07:01

“…Additionally, MD simulations were conducted in order to see the possible effects of ximelagatran on the structure of the peptide binding groove of HLA-DRB1*07:01 and the conformation of bound ligand peptide, and to compare them with those of AdCaPy (one of the major histocompatibility complex loading enhancers [9]) and lapatinib [10]. The interaction modes of ximelagatran in the absence and presence of the ligand peptide were similar to those found in the docking study.…”

“…Ximelagatran binds along the center of the peptide binding groove of HLA-DRB1*07:01 and makes its deepest contact in or near the P4 pocket. In the absence of the ligand peptide, ximelagatran keeps the peptide binding groove in an open state (Figure 4d and Figure 5a) similarly to AdCaPy, which enhances the loading efficiency of ligand peptides onto several HLA-DR molecules [9]. However, unlike AdCaPy, which is small and interacts with the P1 pocket of HLA-DR molecules, ximelagatran interacts along a relatively large part of the peptide binding groove of HLA-DRB1*07:01.…”

“…There also have been several reports showing that small molecules can modify the antigen loading onto HLA molecules [5,6,7,8], and the interaction modes of some compounds with HLA molecules have been evaluated by in silico docking simulation [5], MD simulation [9], or X-ray crystalline structure analysis [6]. We previously reported that in vitro lapatinib enhances the binding of the ligand peptide to HLA-DRB1*07:01, which is strongly associated with lapatinib-induced liver injury, and MD simulations indicated the allele specific modification of the structure of the peptide binding groove of HLA-DRB1*07:01 by lapatinib [10].…”

Virtual Interactomics of Proteins from Biochemical Standpoint

“…In addition to current molecular docking simulations (Table 3), certain docking studies analyzed modulation effects of additional molecules on the evaluated interaction [163–165]. Homology modeling followed by extensive molecular dynamics simulation was used to identify nonpeptidic small organic compounds (among 150 000 compounds) that bind to a human leukocyte antigen HLA-DR1301, and block the presentation of myelin basic protein peptide (aa positions 152–165) to T-cells.…”