abstract
Antiamoebin I (AAM-I) and zervamicin II (Zrv-IIB) are peptaibols that exert antibiotic activity through the insertion/disruption of cell membranes. In this study, we investigated how the folding of these peptaibols are affected when some of their native residues are replaced with proline analogues and asymmetricalD-alpha, alpha-dialkyl glycines (two classes of noncanonical amino acids). Systematic substitutions of native Aib, Pro, Hyp, and Iva residues were performed to elucidate the folding properties of the modified peptaibols incorporating noncanonical residues. The secondary structure of a peptaibol influences its ability to incorporate into membranes and therefore its function. Our findings reveal that native Zrv-IIB unfolds considerably in water. The presence of Iva and the noncanonical proline analogue cis-3-amino-L-proline (ALP) in both peptaibols induces helical structures. Inserting asymmetric glycines such as alpha-methyl-D-leucine (MDL) and alpha-methyl-D-phenylalanine (MDP) into the peptaibols induces folding. This preorganization in water may help to overcome the energy barrier required for peptaibol insertion into the membrane, as well as to facilitate the formation of transmembrane channels.
keywords
CHANNEL-FORMING POLYPEPTIDE; LINEAR CONSTRAINT SOLVER; ION CHANNELS; ANTIMICROBIAL PEPTIDES; MOLECULAR SIMULATION; CRYSTAL-STRUCTURE; ALPHA,ALPHA-DIALKYL GLYCINES; SPATIAL STRUCTURE; HELICAL PEPTIDES; WATER MODELS
subject category
Biochemistry & Molecular Biology; Biophysics; Chemistry; Computer Science
authors
Castro, TG; Micaelo, NM; Melle-Franco, M
our authors
Manuel Melle-Franco
Principal Researcheracknowledgements
This work was mainly supported by Fundacao para a Ciencia e a Tecnologia (FCT) through SFRH/BD/79195/2011, PEst-C/QUI/UI0686/2011, and FCOMP-01-0124-FEDER-022716. The authors are grateful for their access to the Minho University GRIUM cluster and for the contract research grant C2008-UMINHO-CQ-03. MMF acknowledges support from the Portuguese FCT through the program Ciencia 2008 and within the Project Scope UID/CEC/00319/2013. Access to computing resources funded by the Project "Search-ON2: Revitalization of HPC infrastructure of UMinho" (NORTE-07-0162-FEDER-000086) is also gratefully acknowledged.