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Sequence dependent lipid-mediated effects modulate the dimerization of ErbB2 and its associative mutants
Xavier Prasanna1, P J Praveen, Durba Sengupta
1CSIR-National Chemical Laboratory, Dr Homi Bhaba, Road, Pune-411008, India. d.sengupta@ncl.res.in.
Physical Chemistry Chemical Physics : PCCP
|October 8, 2013
Summary
Transmembrane helix association, crucial for biological processes, is influenced by both specific and non-specific environmental factors. Molecular dynamics simulations reveal lipid bilayer thinning and perturbations around ErbB2 mutants, driving helix dimerization.
Area of Science:
- Biophysics
- Molecular Biology
- Computational Biochemistry
Background:
- Transmembrane helix association is vital for cellular functions.
- Factors governing helix association, particularly environmental influences, remain poorly understood.
- ErbB2, an oncogene, plays a role in cancer development.
Purpose of the Study:
- To investigate the association of ErbB2 transmembrane helices and their oncogenic mutants.
- To elucidate the role of non-specific environmental effects in transmembrane helix association.
- To quantify the contribution of protein-protein interactions and environmental factors to helix dimerization.
Main Methods:
- Coarse-grain molecular dynamics simulations were employed.
- Self-assembly simulations were performed to model helix association.
- Dimerization free-energy profiles were calculated to assess association stability.
Main Results:
- Both wildtype and mutant ErbB2 helices exhibit energetically favorable dimerized states.
- Mutant ErbB2 peptides show higher dissociation free energy compared to the wildtype.
- Non-specific environmental effects, including local bilayer thinning and membrane perturbations, contribute to helix association, particularly for mutants.
Conclusions:
- Lipid chain packing emerges as a significant driving force for helix dimerization.
- Both specific protein-protein interactions and non-specific environmental factors are crucial for transmembrane helix association.
- Understanding these forces is key to comprehending ErbB2's role in biological processes and cancer.
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