Curvature sensing is an essential ability of biomolecules to preferentially localize to membrane regions of a specific curvature. It has been shown that amphipathic helices (AHs), helical peptides with both hydrophilic and hydrophobic regions, could sense a positive membrane curvature. The origin of this AH sensing has been attributed to their ability to exploit lipid-packing defects that are enhanced in regions of positive curvature. In this study, we revisit an alternative framework where AHs act as sensors of local internal stress within the membrane, suggesting the possibility of an AH sensing a negative membrane curvature. Using molecular dynamics simulations, we gradually tuned the hydrophobicity of AHs, thereby adjusting their insertion depth so that the curvature preference of AHs is switched from positive to negative. This study suggests that highly hydrophobic AHs could preferentially localize proteins to regions of a negative membrane curvature.

CEITEC Central European Institute of Technology Masaryk University Kamenice 753 5 625 00 Brno Czech Republic

Department of Condensed Matter Physics Faculty of Science Masaryk University Kotlářská 267 2 611 37 Brno Czech Republic

National Centre for Biomolecular Research Faculty of Science Masaryk University Kamenice 5 625 00 Brno Czech Republic

Zobrazit více v PubMed

McMahon H. T.; Boucrot E. Membrane curvature at a glance. J. Cell Sci. 2015, 128, 1065–1070. 10.1242/jcs.114454. PubMed DOI PMC

Jarsch I. K.; Daste F.; Gallop J. L. Membrane curvature in cell biology: An integration of molecular mechanisms. J. Cell Biol. 2016, 214, 375–387. 10.1083/jcb.201604003. PubMed DOI PMC

Bigay J.; Gounon P.; Robineau S.; Antonny B. Lipid packing sensed by ArfGAP1 couples COPI coat disassembly to membrane bilayer curvature. Nature 2003, 426, 563–566. 10.1038/nature02108. PubMed DOI

Peter B. J.; Kent H. M.; Mills I. G.; Vallis Y.; Butler P. J. G.; Evans P. R.; McMahon H. T. BAR domains as sensors of membrane curvature: the amphiphysin BAR structure. Science 2004, 303, 495–499. 10.1126/science.1092586. PubMed DOI

Bigay J.; Casella J.-F.; Drin G.; Mesmin B.; Antonny B. ArfGAP1 responds to membrane curvature through the folding of a lipid packing sensor motif. EMBO J. 2005, 24, 2244–2253. 10.1038/sj.emboj.7600714. PubMed DOI PMC

Blood P. D.; Voth G. A. Direct observation of Bin/amphiphysin/Rvs (BAR) domain-induced membrane curvature by means of molecular dynamics simulations. Proc. Natl. Acad. Sci. U.S.A. 2006, 103, 15068–15072. 10.1073/pnas.0603917103. PubMed DOI PMC

Simunovic M.; Voth G. A.; Callan-Jones A.; Bassereau P. When physics takes over: BAR proteins and membrane curvature. Trends Cell Biol. 2015, 25, 780–792. 10.1016/j.tcb.2015.09.005. PubMed DOI PMC

Simunovic M.; Evergren E.; Golushko I.; Prévost C.; Renard H.-F.; Johannes L.; McMahon H. T.; Lorman V.; Voth G. A.; Bassereau P. How curvature-generating proteins build scaffolds on membrane nanotubes. Proc. Natl. Acad. Sci. U.S.A. 2016, 113, 11226–11231. 10.1073/pnas.1606943113. PubMed DOI PMC

Simunovic M.; Evergren E.; Callan-Jones A.; Bassereau P. Curving the cells inside and out: Roles of BAR-domain proteins in intracellular trafficking, shaping organelles, and cancer. Annu. Rev. Cell Dev. Biol. 2019, 35, 111.10.1146/annurev-cellbio-100617-060558. PubMed DOI

Drin G.; Casella J.-F.; Gautier R.; Boehmer T.; Schwartz T. U.; Antonny B. A general amphipathic α-helical motif for sensing membrane curvature. Nat. Struct. Mol. Biol. 2007, 14, 138–146. 10.1038/nsmb1194. PubMed DOI

Drin G.; Antonny B. Amphipathic helices and membrane curvature. FEBS Lett. 2010, 584, 1840–1847. 10.1016/j.febslet.2009.10.022. PubMed DOI

Kozlov M. M.; Campelo F.; Liska N.; Chernomordik L. V.; Marrink S. J.; McMahon H. T. Mechanisms shaping cell membranes. Curr. Opin. Cell Biol. 2014, 29, 53–60. 10.1016/j.ceb.2014.03.006. PubMed DOI PMC

Guo X.; Steinkühler J.; Marin M.; Li X.; Lu W.; Dimova R.; Melikyan G. B. Interferon-induced transmembrane protein 3 blocks fusion of diverse enveloped viruses by altering mechanical properties of cell membranes. ACS Nano 2021, 15, 8155–8170. 10.1021/acsnano.0c10567. PubMed DOI PMC

Cui H.; Lyman E.; Voth G. A. Mechanism of membrane curvature sensing by amphipathic helix containing proteins. Biophys. J. 2011, 100, 1271–1279. 10.1016/j.bpj.2011.01.036. PubMed DOI PMC

Vanni S.; Hirose H.; Barelli H.; Antonny B.; Gautier R. A sub-nanometre view of how membrane curvature and composition modulate lipid packing and protein recruitment. Nat. Commun. 2014, 5, 4916.10.1038/ncomms5916. PubMed DOI

Vanni S.; Vamparys L.; Gautier R.; Drin G.; Etchebest C.; Fuchs P. F.; Antonny B. Amphipathic lipid packing sensor motifs: probing bilayer defects with hydrophobic residues. Biophys. J. 2013, 104, 575–584. 10.1016/j.bpj.2012.11.3837. PubMed DOI PMC

Campelo F.; McMahon H. T.; Kozlov M. M. The hydrophobic insertion mechanism of membrane curvature generation by proteins. Biophys. J. 2008, 95, 2325–2339. 10.1529/biophysj.108.133173. PubMed DOI PMC

Campelo F.; Kozlov M. M. Sensing membrane stresses by protein insertions. PLoS Comput. Biol. 2014, 10, e100355610.1371/journal.pcbi.1003556. PubMed DOI PMC

Mandal T.; Spagnolie S. E.; Audhya A.; Cui Q. Protein-induced membrane curvature in coarse-grained simulations. Biophys. J. 2021, 120, 3211–3221. 10.1016/j.bpj.2021.05.029. PubMed DOI PMC

Risselada H. J.; Marrink S. J. Curvature effects on lipid packing and dynamics in liposomes revealed by coarse grained molecular dynamics simulations. Phys. Chem. Chem. Phys. 2009, 11, 2056–2067. 10.1039/b818782g. PubMed DOI

Yesylevskyy S. O.; Rivel T.; Ramseyer C. The influence of curvature on the properties of the plasma membrane. Insights from atomistic molecular dynamics simulations. Sci. Rep. 2017, 7, 16078.10.1038/s41598-017-16450-x. PubMed DOI PMC

Gómez-Llobregat J.; Elías-Wolff F.; Lindén M. Anisotropic membrane curvature sensing by amphipathic peptides. Biophys. J. 2016, 110, 197–204. 10.1016/j.bpj.2015.11.3512. PubMed DOI PMC

Stroh K. S.; Risselada H. J. Quantifying Membrane Curvature Sensing of Peripheral Proteins by Simulated Buckling and Umbrella Sampling. J. Chem. Theory Comput. 2021, 17, 5276–5286. 10.1021/acs.jctc.1c00021. PubMed DOI

Jensen L. E.; Rao S.; Schuschnig M.; Cada A. K.; Martens S.; Hummer G.; Hurley J. H. Membrane curvature sensing and stabilization by the autophagic LC3 lipidation machinery. Sci. Adv. 2022, 8, eadd143610.1126/sciadv.add1436. PubMed DOI PMC

Abraham M. J.; Murtola T.; Schulz R.; Páll S.; Smith J. C.; Hess B.; Lindahl E. GROMACS: High performance molecular simulations through multi-level parallelism from laptops to supercomputers. SoftwareX 2015, 1, 19–25. 10.1016/j.softx.2015.06.001. DOI

Marrink S. J.; Risselada H. J.; Yefimov S.; Tieleman D. P.; De Vries A. H. The MARTINI force field: coarse grained model for biomolecular simulations. J. Phys. Chem. B 2007, 111, 7812–7824. 10.1021/jp071097f. PubMed DOI

Monticelli L.; Kandasamy S. K.; Periole X.; Larson R. G.; Tieleman D. P.; Marrink S.-J. The MARTINI coarse-grained force field: extension to proteins. J. Chem. Theory Comput. 2008, 4, 819–834. 10.1021/ct700324x. PubMed DOI

De Jong D. H.; Singh G.; Bennett W. D.; Arnarez C.; Wassenaar T. A.; Schafer L. V.; Periole X.; Tieleman D. P.; Marrink S. J. Improved parameters for the martini coarse-grained protein force field. J. Chem. Theory Comput. 2013, 9, 687–697. 10.1021/ct300646g. PubMed DOI

Cho N.-J.; Dvory-Sobol H.; Xiong A.; Cho S.-J.; Frank C. W.; Glenn J. S. Mechanism of an amphipathic α-helical peptide’s antiviral activity involves size-dependent virus particle lysis. ACS Chem. Biol. 2009, 4, 1061–1067. 10.1021/cb900149b. PubMed DOI

Bhaskara R. M.; Grumati P.; Garcia-Pardo J.; Kalayil S.; Covarrubias-Pinto A.; Chen W.; Kudryashev M.; Dikic I.; Hummer G. Curvature induction and membrane remodeling by FAM134B reticulon homology domain assist selective ER-phagy. Nat. Commun. 2019, 10, 2370.10.1038/s41467-019-10345-3. PubMed DOI PMC

Wimley W. C.; White S. H. Experimentally determined hydrophobicity scale for proteins at membrane interfaces. Nat. Struct. Biol. 1996, 3, 842–848. 10.1038/nsb1096-842. PubMed DOI

Sodt A. J.; Pastor R. W. Molecular modeling of lipid membrane curvature induction by a peptide: more than simply shape. Biophys. J. 2014, 106, 1958–1969. 10.1016/j.bpj.2014.02.037. PubMed DOI PMC

Huang J.; Rauscher S.; Nawrocki G.; Ran T.; Feig M.; De Groot B. L.; Grubmüller H.; MacKerell A. D. Jr CHARMM36m: an improved force field for folded and intrinsically disordered proteins. Nat. Methods 2017, 14, 71–73. 10.1038/nmeth.4067. PubMed DOI PMC

Souza P. C. T.; et al. Martini 3: a general purpose force field for coarse-grained molecular dynamics. Nat. Methods 2021, 18, 382–388. 10.1038/s41592-021-01098-3. PubMed DOI

Mattila P. K.; Pykalainen A.; Saarikangas J.; Paavilainen V. O.; Vihinen H.; Jokitalo E.; Lappalainen P. Missing-in-metastasis and IRSp53 deform PI (4, 5) P2-rich membranes by an inverse BAR domain–like mechanism. J. Cell Biol. 2007, 176, 953–964. 10.1083/jcb.200609176. PubMed DOI PMC

Prévost C.; Zhao H.; Manzi J.; Lemichez E.; Lappalainen P.; Callan-Jones A.; Bassereau P. IRSp53 senses negative membrane curvature and phase separates along membrane tubules. Nat. Commun. 2015, 6, 8529.10.1038/ncomms9529. PubMed DOI PMC

Jackman J. A.; Costa V. V.; Park S.; Real A. L. C.; Park J. H.; Cardozo P. L.; Ferhan A. R.; Olmo I. G.; Moreira T. P.; Bambirra J. L.; et al. Therapeutic treatment of Zika virus infection using a brain-penetrating antiviral peptide. Nat. Mater. 2018, 17, 971–977. 10.1038/s41563-018-0194-2. PubMed DOI

Jackman J. A.; Shi P.-Y.; Cho N.-J. Targeting the Achilles heel of mosquito-borne viruses for antiviral therapy. ACS Infect. Dis. 2019, 5, 4–8. 10.1021/acsinfecdis.8b00286. PubMed DOI

Shin S.; Ko H.; Kim C. H.; Yoon B. K.; Son S.; Lee J. A.; Shin J. M.; Lee J.; Song S. H.; Jackman J. A.; et al. Curvature-sensing peptide inhibits tumour-derived exosomes for enhanced cancer immunotherapy. Nat. Mater. 2023, 22, 656.10.1038/s41563-023-01515-2. PubMed DOI

Schmidt N. W.; Wong G. C. Antimicrobial peptides and induced membrane curvature: Geometry, coordination chemistry, and molecular engineering. Curr. Opin. Solid State Mater. Sci. 2013, 17, 151–163. 10.1016/j.cossms.2013.09.004. PubMed DOI PMC

Free Energy of Membrane Pore Formation and Stability from Molecular Dynamics Simulations

Peptide translocation across asymmetric phospholipid membranes