Predictive analysis of binding affinity among human cytomegalovirus (HCMV) proteins and class-I major histocompatibility complex (MHC-I) molecules

References

1. Sequence No. of Amino Acids Molecular Weight (Da) Theoretical pI Instability Index Gravy Total Atom Nos. Extinction Coefficient (Cys-Cys) Extinction Coefficient (Reduced Cys) US2 QNT12687.1 199 23110.95 6.82 28.71 0.131 3236 68660 68410 US3 AAS49002.1 186 21514.98 8.59 44.20 0.076 3032 39545 39420 US6 AAS49004.1 183 20611.96 8.73 45.66 -0.138 2889 17710 16960 US10 YP_081595.1 185 20771.09 8.1 47.21 0.051 2918 40380 39880 US11 YP_081596.1 215 25288.44 5.46 56.46 -0.029 3558 70610 70360 Table 4: Presents structural alignment results of HCMV proteins using TM-align, with US3 and US10 showing the highest similarity (US10 perfectly aligned), moderate similarity for US6 and US2, and the lowest for US11 Proteins Sample Acc. No. Control Acc. No. Length of Chain_1 Length of Chain_2 Aligned Length RMSD Seq. ID TM-score (Chain_1) TM-score (Chain_2) US2 A398799 B398799 275 613 159 6.55 0.031 0.32891 0.18085 US3 A768951 B768951 275 275 275 0.00 1.000 1.00000 1.00000 US6 A627561 B627561 119 738 90 4.86 0.056 0.41385 0.09977 US10 A456694 B456694 362 362 362 0.00 1.000 1.00000 1.00000 US11 A342978 B342978 119 213 62 4.70 0.065 0.30271 0.19793 Table 5: Details superimposition of HCMV proteins on ten MHC Class I molecules, identifying closest structural matches (e.g., US2/US3 with 1m3), illustrating molecular mimicry and potential immune interactions S. No. MHC CLASS I molecules HCMV proteins Chain 1 Chain 2 Aligned Length RMSD TM- Score 1 TM- Score 2
2. 8rbu 1im3 A39262 B39262 275 1.09 0.97375 0.97375 8rbu 2not A43136 B43136 87 4.52 0.22385 0.41101 8rbu 3chx A775119 B775119 125 6.17 0.26921 0.22068 8rbu 2dyt A225357 B225357 93 5.54 0.21168 0.253
3. 6at5 1im3 A915955 B915955 275 0.93 0.97831 0.97831 6at5 2not A76528 B76528 62 4.12 0.16994 0.32446 6at5 3chx A375128 B375128 125 6.26 0.26725 0.21876 6at5 2dyt A938623 B938623 94 5.84 0.20983 0.25083
4. 8rh6 1im3 A830088 B830088 275 1.07 0.97431 0.97431 8rh6 2not A265052 B265052 84 4.97 0.20479 0.36051 8rh6 3chx A770980 B770980 128 6.7 0.25794 0.21251 8rh6 2dyt A614219 B614219 94 5.79 0.21694 0.26199
5. 6avf 1im3 A995997 B995997 91 1.98 0.80504 0.30499 6avf 2not A823717 B823717 49 4.38 0.27706 0.23798 6avf 3chx A162769 B162769 86 3.95 0.52829 0.1888 6avf 2dyt A849825 B849825 73 4.34 0.43199 0.23963
6. 8rcv 1im3 A567132 B567132 275 0.97 0.97318 0.97665 8rcv 2not A710917 B710917 84 5.11 0.20065 0.34949 8rcv 3chx A206273 B206273 125 6.16 0.26646 0.21923 8rcv 2dyt A261797 B261797 96 5.59 0.22061 0.26591
7. 8ref 1im3 A38683 B38683 275 0.87 0.97754 0.98104 8ref 2not A657214 B657214 83 5.02 0.19822 0.34421 8ref 3chx A651801 B651801 125 6.1 0.26846 0.22067 8ref 2dyt A845288 B845288 94 5.46 0.21787 0.26214 340 Biswas et al. / Indian Journal of Microbiology Research 2025;12(3):334–345
8. 7tlt 1im3 A790795 B790795 272 0.89 0.97686 0.96987 7tlt 2not A643556 B643556 77 5.31 0.18021 0.30753 7tlt 3chx A272931 B272931 132 6.67 0.26233 0.21609 7tlt 2dyt A736837 B736837 96 5.9 0.21743 0.25974
9. 6avg 1im3 A319539 B319539 94 2.16 0.79055 0.31365 6avg 2not A665036 B665036 52 4.81 0.25042 0.22573 6avg 3chx A103048 B103048 90 3.94 0.53554 0.19852 6avg 2dyt A7491 B7491 72 4.24 0.42602 0.24219
10. 7tlt 1im3 A893416 B893416 275 0.95 0.97705 0.97705 7tlt 2not A267335 B267335 82 4.91 0.20548 0.3755 7tlt 3chx A269864 B269864 126 6.24 0.27106 0.22162 7tlt 2dyt A521269 B521269 94 5.88 0.21576 0.26075
11. 7rtd 1im3 A549898 B549898 274 0.73 0.98646 0.98292 7rtd 2not A424143 B424143 84 5.03 0.20322 0.35317 7rtd 3chx A510367 B510367 122 6.1 0.26341 0.21552 7rtd 2dyt A172716 B172716 100 5.76 0.22927 0.27483 Figure 1: Sequence alignment and hydropathicity of HCMV proteins. (A): US2 shows a conserved core region modelled on 1im3.1, with colour-coded domains. (B): US3 has lower alignment and more gaps than US2. (C): US6 exhibits the lowest hydropathicity (−0.138), highlighting possible membrane interaction sites. (D): US2 has the highest hydropathicity (0.131), dominated by hydrophilic residues Figure 2: Domain annotations and 3D models of HCMV proteins. US2 & US3 belong to Cytomega_US3 family. US6 models to US6 superfamily; US10 to US10 domain; US11 to CMV_US superfamily. Homology modelling shows US2 complexed with MHC-I, US6 related to neurotoxic phospholipase A2, US10 to methane monooxygenase, and US11 to autophagy protein Atg3 Biswas et al. / Indian Journal of Microbiology Research 2025;12(3):334–345 341 Figure 3: Transmembrane helix predictions and Ramachandran plots. US2 and US3: single TM helix (~161-184). US6 & US11: one TM helix each (147-169 and 181-203, respectively). US10: two TM helices (127-149 and 159-181). Ramachandran plots show >88% residues in favoured regions for all proteins, indicating stable folds Figure 4: Multiple sequence alignment (MSA) and phylogeny of US2, US3, US6, US10, and US11. (A): US2, US3, and US6 share conserved regions; US10 has many indels and the shortest N-terminus. (B): Phylogenetic tree groups US2 and US3 closely; US6 and US11 cluster separately; US10 is a distant outlier 342 Biswas et al. / Indian Journal of Microbiology Research 2025;12(3):334–345 Figure 5: Structural comparison of HCMV protein models. US2 and US3: β-helix rich. US6: compact α-helical globular structure. US10: largest, complex with α-helices and β-sheets. US11: extended, flexible conformation Figure 6: Superimposition of HCMV proteins with MHC Class I molecules. (A): US2 and US3 are closely aligned with MHC- I. (B): US6 fits tightly in the MHC core. (C): US10 shows poor alignment, weak interaction. (D): US11 moderate alignment, less stable interaction Biswas et al. / Indian Journal of Microbiology Research 2025;12(3):334–345 343
12. Discussion
13. Structural quality and evolutionary analysis of HCMV immune evasion proteins Ramachandran plot analysis demonstrated that most HCMV proteins are well-folded and structurally stable. US6 and US11 exhibited exceptional structural quality, with over 91% of residues residing in favoured conformational regions. US2 and US3 also showed high-quality folding, with approximately 90% of residues in favourable geometries. These proteins benefit from the strategic distribution of glycine and proline residues, glycine conferring flexibility through hinge-like regions, and proline introducing rigidity that stabilizes protein folds. 44,45 In contrast, US10 displayed comparatively lower structural regularity, with only 88.4% of residues in favoured regions and a negative G-factor score, indicating atypical geometric features. Multiple sequence alignment (MSA) revealed conserved domains primarily between residues 60–70 and 120–140 across the proteins, implicating these regions in essential functional roles. US2, US3, and US6 share notable sequence conservation and structural similarity, supporting a common evolutionary origin and coordinated functional mechanisms. Phylogenetic analysis further corroborated these relationships, US2 and US3 formed a sister clade, closely associated with US6, reflecting their cooperative roles in MHC Class I modulation. US11 clustered more distantly yet remained related, while US10 emerged as a distinct outlier, underscoring its evolutionary divergence and unique functional specialization. TM-align structural analysis provided quantitative measurements of structural similarity among HCMV proteins, with results summarized in Table 4. The most striking finding was that US2 and US10 exhibited perfect structural alignment with TM-scores of 1.000 and RMSD values of 0.00, indicating identical three-dimensional structures. This analysis suggested these proteins share high structural conservation despite their evolutionary distance, though this finding may reflect limitations in structural prediction models rather than true structural identity.
14. Structural comparison of HCMV immune evasion proteins Complementing these findings, TM-align structural comparisons quantified protein similarities (Table 4). Notably, US2 and US10 exhibited perfect structural alignment with TM-scores of 1.000 and RMSD values of
15. 00, suggesting identical predicted three-dimensional conformations. This high degree of structural similarity, despite their evolutionary distance, may reflect inherent limitations in predictive modelling rather than true structural identity. In contrast, US2, US6, and US11 displayed moderate to low structural similarity, consistent with their evolutionary divergence and distinct functional roles. Figure 5 illustrates detailed structural comparisons: US2 and US3 share a combined fold dominated by beta-barrel elements, likely conferring stability essential for their trafficking and interaction with MHC Class I molecules. US6 adopts a compact, globular structure rich in alpha-helices, facilitating its role in molecular recognition and regulatory interactions. US10’s structure is notably complex, integrating extensive alpha-helical and beta-sheet content, reflective of its dual transmembrane domains and specialized targeting of HLA-G molecules. Finally, US11 exhibits an extended alpha-helical conformation that provides conformational flexibility, enabling versatile binding to diverse host targets, a feature critical for dynamic immune evasion.
16. Comparative structural analysis of HCMV proteins and MHC class I molecules The comparative structural analysis between HCMV proteins and MHC Class I molecules (Table 5) revealed variable degrees of similarity corresponding to their functional roles. MHC molecules exhibited high structural conservation both among themselves and with the US2/US3 complex (PDB ID: 1IM3), with TM-scores consistently above 0.9 and minimal RMSD values. This strong resemblance underscores a sophisticated molecular mimicry by US2 and US3, enabling their integration into the host MHC processing pathway. US6 displayed moderate similarity to MHC molecules, with TM- scores indicative of complementary but not identical structural features, reflecting an evolutionary strategy distinct from direct mimicry. In contrast, US10 demonstrated the lowest structural similarity, with RMSD values generally exceeding 6Å, highlighting its specialized targeting of alternative immune recognition components. US11 showed slightly better alignment than US10, but low TM-scores and RMSD values above 5 Å confirmed its divergence from MHC-like structures, consistent with its unique functional adaptations. Alignments were performed between ten MHC Class I variants and four HCMV proteins (US2, US6, US10, US11), yielding 40 interaction models. The TM and RMSD metrics were consistent across different MHC variants for each viral protein, indicating stable structural relationships independent of the MHC allele. Representative alignment examples for each protein-MHC pair are illustrated in Figure 6, effectively capturing characteristic interaction patterns while minimizing redundancy.US2 and US3 proteins demonstrate exceptional structural confidence and therapeutic potential. Both belong to the pfam05963 domain family and achieved 100% confidence in Phyre2 modelling with 48% and 47% coverage, respectively, using immunoglobulin-like beta-sandwich fold templates (Figure 1 A, B). RCSB modelling with 1im3 revealed hetero-trimer (1-1-1-mer) configurations involving identical ligands: LEU- LEU-PHE-GLY-TYR-PRO-VAL-TYR-VAL. Ramachandran plot analysis showed 90.3% of residues in favoured regions with single transmembrane helix architecture and high TM scores compared to 1im3 (Figure 3 E). These characteristics position US2 and US3 as prime candidates for epitope-based vaccine design and therapeutic applications. 344 Biswas et al. / Indian Journal of Microbiology Research 2025;12(3):334–345
17. Conserved domains and vaccine potential of HCMV immune evasion proteins Multiple sequence alignment and phylogenetic analyses revealed conserved regions among US2, US3, and US6, particularly between residues 60-140, reflecting strong evolutionary conservation and functional importance in disrupting MHC-I antigen presentation (Figure 4 A, B). These ER-resident glycoproteins’ conserved domains make them promising targets for epitope-based vaccine development. The high structural similarity of US2 and US3 to MHC-I (PDB: 1IM3), coupled with stable modelling results, supports their potential use as subunit vaccine antigens to prime immune responses against early viral immune evasion. US10, although showing low structural similarity to MHC-I, possesses unique immunomodulatory functions via its conserved tri-leucine motif and complex dual transmembrane topology. It specifically downregulates HLA-G, modulating NK cell responses and expanding the immunogenic scope of potential vaccines to include both T cell and NK cell evasion mechanisms. 18 Incorporating proteins like US10 could enhance vaccine breadth by targeting multiple immune evasion pathways. US10 is a distinctive and less-characterised HCMV protein expressed early during infection. 13 Unlike other US proteins that degrade MHC-I, US10 delays HLA-G trafficking through its tri-leucine motif in the cytoplasmic tail, enabling NK cell evasion. 18 Structurally, US10 is a 185-residue protein containing a conserved Pfam17617 domain (residues 25- 185). Phyre2 modelling yielded low confidence (6.1%) with partial coverage (45%), reflecting structural complexity and unusual conformations. Ramachandran analysis showed significant deviations in allowed regions, suggesting structural features challenging current prediction methods.
18. Clinical and therapeutic implications Given their early expression and roles in immune evasion, these HCMV proteins offer valuable targets for diagnostics and therapeutics, especially in immunocompromised patients and congenital infections. 1,2 Assays targeting specific transcripts or epitopes (e.g., via ELISA or qPCR) could improve detection sensitivity. US10’s modulation of HLA-G makes it a particularly important biomarker for assessing NK cell-related immune dysfunction in vulnerable populations. 37 Therapeutically, US6 and US10 represent promising targets to counteract immune evasion. US6 inhibits antigen processing by blocking TAP-mediated peptide transport, while US10 internalizes MHC-I molecules through its tri- leucine motif, impacting both T cell and NK cell responses. 37 Structural analyses characterize US6 as hydrophilic and thermally stable, whereas US10’s dual transmembrane helices and disordered regions highlight its structural divergence and poor alignment with MHC-I molecules (Figure 3; Table 3, Table 5), suggesting novel mechanisms suitable for targeted intervention.
19. Conclusion This study outlines the roles of HCMV immune evasion proteins US2, US3, US6, US10, and US11 about MHC-I molecules. US2 and US3 show strong alignment and stability with MHC-I, suggesting their potential as vaccine or therapeutic candidates. US6 and US11 effectively disrupt antigen presentation but vary in stability and interaction. US10 features dual transmembrane helices and targets the non-classical MHC-I molecule HLA-G, indicating a specialized mechanism against NK cell responses. This underscores the need for further validation. Overall, these findings highlight US10 and other viral proteins as targets for diagnostics, therapies, and vaccines.
20. Source of Funding No funds were available for this research.
21. Conflicts of Interest The authors reported no potential conflict of interest.
22. Author Contributions Conceptualization, A.S., M.S. and B.B.; execution of methodology, B.B. and A.B.; investigation, B.B., A.B. and A.S.; writing-original draft preparation, B.B., A.B., D.D. and M.S.; writing-review and editing, A.S., D.D. and M.S. All authors have read and agreed to the published version of the manuscript.
23. Acknowledgements The authors would like to thank Department of Biosciences, JIS University for providing high speed internet facility and additional lab support. References
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