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Impact of PIP2 Lipids, Force Field Parameters, and Mutational Analysis on the Binding of the Osh4’s α6–α7 Domain

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journal contribution
posted on 13.05.2021, 21:34 by Robert J. Allsopp, Jeffery B. Klauda
All-atom molecular dynamics simulations are used with the highly mobile membrane mimetic method to study the α6–α7 peptide of the critical yeast Osh4 peripheral membrane protein. This research focuses on the impact of 1-palmitoyl-2-oleoyl-sn-glycero-phosphatidylinoside 4,5-bisphosphate (PIP2) lipids and 1-palmitoyl-2-oleoyl-sn-glycero-3-phospho-l-serine on the protein’s ability to bind to the membrane. Details of the binding mechanism are described qualitatively and quantitatively by measuring the position of the deepest residues, angle of the peptide during binding, root mean square deviation of the atomic positions within the peptide, and interaction energy, while changing variables, such as the force field used and the presence of the PIP2 lipids. The negatively charged PIP2 has a large head group that is a few Ångstroms above the main membrane phosphates enabling the PIP2 lipids to interact with the peptide before it binds deeper into the membrane. The PIP2 lipids can alter the position of the peptide during binding by recruiting charged residues on the α7 helix, such as R344 and R347. Residues R347 and R344 are unusual because they are slightly out of the reach of the main membrane phosphates but optimally positioned to interact with the PIP2 lipids. The salt-bridge interactions can also typically occur between cationic peptide residues such as R314, K325, and K336. The force field interaction effect on peptide binding was also investigated by changing the standard CHARMM36m to an improved description between some amino acids and lipid moieties (Phys. Chem. Chem. Phys. 20, 8432–8449). This resulted in the total number of salt bridges and hydrogen bonds being drastically reduced, the interaction energy was also reduced, and there was more balance between electrostatic and nonpolar interactions, but the general bound structure is maintained. This work is an important initial step to understand the effect of the Osh4 protein on the membrane binding and to quantify the effect of PIP2 lipids on this domain.

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