Specification of binding modes between a transmembrane peptide mimic of ATP6V0C and polytopic E5 of human...

Area of Science:

• Biochemistry
• Molecular Biology
• Structural Biology

Background:

• The E5 oncoprotein of human papillomavirus-16 (HPV-16) plays a crucial role in viral oncogenesis.
• E5 interacts with cellular proteins, including the vacuolar H+-ATPase (V-ATPase), to modulate cellular functions.
• Understanding the molecular basis of E5-V-ATPase interaction is vital for developing antiviral strategies.

Purpose of the Study:

• To investigate the interaction between HPV-16 E5 protein's transmembrane domains (TMDs) and a peptide mimicking the TMD of the ATP6V0C subunit of human V-ATPase.
• To characterize the binding sites, energies, and thermodynamic driving forces of this interaction using computational methods.

Main Methods:

• Molecular docking simulations to predict binding interfaces.
• Potential of Mean Force (PMF) calculations to estimate binding energies.
• Coarse-grained molecular dynamics (CG-MD) simulations and Principal Component Analysis (PCA) to determine thermodynamic contributions (enthalpy and entropy).

Main Results:

• Docking revealed that the ATP6V0C peptide binds within the second and third TMDs of HPV-16 E5, mediated by hydrophobic residues.
• Binding energy calculations showed marginal differences between wild-type and mutant peptides, as well as between E5 TMD dimers and the peptide.
• Thermodynamic analysis indicated that binding to E5 TMD3 is enthalpy-driven, while binding to E5 TMD2 is entropy-guided.

Conclusions:

• The study elucidates the specific binding interactions between HPV-16 E5 and ATP6V0C, identifying key residues and domains involved.
• Computational findings suggest that while binding affinities are weak, the thermodynamic landscapes differ for interactions with distinct E5 TMDs.
• These insights contribute to understanding HPV-16 E5 function and provide a basis for potential therapeutic interventions targeting viral-host protein interactions.