Analysis of hydrophobic and hydrophilic moments of short penetrating peptides for enhancing mitochondrial localization: prediction and validation

Marco Pirisinu, Pilar Blasco, Xueli Tian, Yang Sen, Ann M. Bode, Kangdong Liu, Zigang Dong

Research output: Contribution to journalArticlepeer-review

1 Scopus citations

Abstract

Pharmaceutical interest in targeting mitochondria is increasing because of their contribution in incurable diseases. However, the inner mitochondrial layer represents a major hurdle to overcome for most drugs. Penetrating peptides are a promising strategy for drug delivery, but the absence of standard principles and reliable prediction tools limits the design and discovery of sequences with improved organelle specificity. In our hypothesis, peptide local flexibility represents a valuable source to predict peptide performance. Here, a pool of short nonnatural peptides was designed with the same amino acid content but different positioning. Molecular dynamics and membrane-transfer simulations were used to generate the low-energy conformers in extra, intracellular, and membrane-inserted environments. The contributions of the hydrophobic and hydrophilic side chain–exposed surfaces revealed that the amino acid's relative position significantly affected the simulated peptide's dynamics. Based on the structural versatility, we predicted the peptides' behavior and the sequence with the most efficient membrane penetration and mitochondrial localization. The prediction and the improved performance of our peptides were experimentally confirmed and compared with a reported mitochondrial-targeting sequence. We demonstrated that an accurate understanding of the structural versatility is a valid aid for future works in designing sequences with improved mitochondrial targeting.—Pirisinu, M., Blasco, P., Tian, X., Sen, Y., Bode, A. M., Liu, K., Dong, Z. Analysis of hydrophobic and hydrophilic moments of short penetrating peptides for enhancing mitochondrial localization: prediction and validation. FASEB J. 33, 7970–7984 (2019). www.fasebj.org.

Original languageEnglish (US)
Pages (from-to)7970-7984
Number of pages15
JournalFASEB Journal
Volume33
Issue number7
DOIs
StatePublished - Jul 1 2019

Bibliographical note

Funding Information:
This work was supported by the Key Program of Henan Province (Grant 161100510300) and the National Natural Science Foundation of China (Grants 81572812 and 81872335). The authors declare no conflicts of interest.

Publisher Copyright:
© FASEB

Keywords

  • cell-penetrating peptides
  • drug delivery
  • molecular dynamics
  • specificity

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