We have carried out molecular dynamics simulations of the naturally occurring protegrin PG-1 peptide and two of its mutants, PC-9 and PC-13 in the presence of a dodecyl-phosphocholine (DPC) micelle. The effects of mutations that disrupt the -sheet structure in the case of PC-9 and reduce the charge at the C-terminus in the case of PC-13 are analyzed. It is found that the surface-bound conformations of the peptides are severely affected by both mutations. PG-1 exhibits a conformation in which the C-terminus and the -hairpin turn interact strongly with the micelle lipid head groups, while its N-terminal strand bends away from the micelle and resides in the aqueous region; PC-13 exhibits strong interactions with the micelle at its N-terminus as well as the -hairpin turn region, while retaining a much more compact conformation than PG-1; PC-9 achieves a highly distorted conformation relative to the homologous PG-1 structure, which allows both its termini and the -hairpin region to interact with the micelle. These significant differences observed as a result of seemingly minor mutations to the sequences of the three peptides are explained in terms of the interplay between residue charges, structural rigidity and amphiphilic interactions. Conservative inferences are made bridging these biophysical interactions and the pharmacological profiles of the peptides.
Bibliographical noteFunding Information:
This work was supported by grants from NSF (EEC-0234112) and NIH (GM 070989). Computational support from the Minnesota Supercomputing Institute (MSI) is gratefully acknowledged. This work was also partially supported by National Computational Science Alliance under MCA04N033S and utilized the National Science Foundation HP GS1280 system and the National Science Foundation Terascale Computing System at the Pittsburgh Supercomputing Center. We thank Prof. Alan Waring and Prof. Robert Lehrer for useful discussions.
- Antimicrobial peptides
- DPC micelle
- Molecular dynamics simulations