Transportan 10 (TP10) is a well-known 21-residue cationic cell-penetrating peptide that is believed to translocate across the bilayers of lipid vesicles. Recent studies of TP10W and its variants suggest that peptide translocation is likely to be determined by whether the cationic residues in the inserted state can be stabilized via salt-bridges to the phosphates of lipid headgroups. In the present work, we tested this charge-distribution hypothesis via multi-microsecond molecular dynamics (MD) simulations of TP10W and its single point mutated variants, TP10W-K12A18 and TP10W-K19L. To select a force field that can show the subtle differences among three variants of TP10W, we first ran a series of 3-4 ms long simulations of a single TP10W, initially placed in water, interacting with a POPC bilayer using five different common force fields (FF). Our simulations showed that the CHARMM36 FF predicts the helicity of TP10W on a POPC membrane that is consistent with the experimental helicity measurement. In particular, CHARMM36 was the only FF that predicted the same peptide structure at the end of two independent simulations. Furthermore, CHARMM36 simulations showed spontaneous folding of TP10W on the membrane from fully extended forms, revealing the detailed folding mechanism.  We carried out subsequent investigations of TP10W variants with the CHARMM36 FF where two simulations were performed for each peptide: one with the peptide placed in water and another with the peptide initially inserted vertically into the bilayer. These simulations showed noticeable difference in the peptide structures in POPC, leading to varying degrees of membrane disruption and salt-bridge formation with the lipid head-groups. Comparisons to experimental data, including the peptide helicity, translocation efficiency, and binding affinity, will be made and the implication of MD results will be discussed in relation to the charge-distribution hypothesis.

Molecular dynamics studies of cell-penetrating peptide TP10W and its variants interacting with POPC membrane: Effect of charge distribution

Macromolecular Chemistry: The Second Century

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ACS Spring 2020 National Meeting & Expo

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