Many membrane peptides and proteins generate membrane curvature to carry out their function. Examples include cationic peptides that disrupt or cross lipid membranes by forming permanent or transient pores and viral fusion proteins that merge the virus envelope and the target cell membrane to cause virus entry. Thus, elucidating the fundamental mechanism of membrane- curvature induction has broad significance for designing resistance-free antibiotics and for developing new vaccines and antiviral drugs. The long-term objective of this project is to understand and quantify lipid-specific interactions of curvature-inducing membrane peptides. We will use solid-state NMR as our main tool, because it is uniquely capable of simultaneously probing the high-resolution structures of membrane proteins and revealing the physical properties of the lipid membrane in which these proteins are embedded. We propose four specific aims. 1) We will investigate cationic-peptide-induced lipid clustering in bacteria- mimetic membranes. Potential segregation of anionic and zwitterionic lipids of bacterial membranes may be a significant factor in promoting membrane curvature. Isotope-edited NMR experiments will be conducted to measure lipid dynamics and peptide-lipid interactions. Representative antimicrobial and cell-penetrating peptides such as PG-1 and HIV TAT will be examined. 2) We will develop 31P exchange NMR techniques to measure the curvature of mixed lipid membranes and the localization of cationic peptides in curvature-distinct domains. 3) We will determine the membrane-bound conformation, dynamics, and depth of insertion of the fusion peptide and transmembrane domain of the fusion protein of the paramyxovirus, PIV5. Structure information of the PIV5 fusion protein will provide insight into the mechanism of action of class I viral fusion proteins. 4) We will investigate the lipid interactions of the PIV5 fusion peptide using 2H, 31P, and 1H NMR experiments. Membrane curvature, peptide localization and membrane hydration will be measured to understand how the peptide modifies the membrane structure to cause fusion.

Public Health Relevance

Elucidating the structures and membrane interactions of antimicrobial peptides, cell-penetrating peptides, and viral fusion peptides may help the development of new resistance-free antibiotics, better drug-delivery agents, and new vaccines and antiviral drugs.

National Institute of Health (NIH)
National Institute of General Medical Sciences (NIGMS)
Research Project (R01)
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Special Emphasis Panel (ZRG1)
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Chin, Jean
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Massachusetts Institute of Technology
Schools of Arts and Sciences
United States
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Kwon, Byungsu; Lee, Myungwoon; Waring, Alan J et al. (2018) Oligomeric Structure and Three-Dimensional Fold of the HIV gp41 Membrane-Proximal External Region and Transmembrane Domain in Phospholipid Bilayers. J Am Chem Soc 140:8246-8259
Roos, Matthias; Wang, Tuo; Shcherbakov, Alexander A et al. (2018) Fast Magic-Angle-Spinning 19F Spin Exchange NMR for Determining Nanometer 19F-19F Distances in Proteins and Pharmaceutical Compounds. J Phys Chem B 122:2900-2911
Gelenter, Martin D; Hong, Mei (2018) Efficient 15N-13C Polarization Transfer by Third-Spin-Assisted Pulsed Cross-Polarization Magic-Angle-Spinning NMR for Protein Structure Determination. J Phys Chem B 122:8367-8379
Lee, Myungwoon; Yao, Hongwei; Kwon, Byungsu et al. (2018) Conformation and Trimer Association of the Transmembrane Domain of the Parainfluenza Virus Fusion Protein in Lipid Bilayers from Solid-State NMR: Insights into the Sequence Determinants of Trimer Structure and Fusion Activity. J Mol Biol 430:695-709
Shcherbakov, Alexander A; Hong, Mei (2018) Rapid measurement of long-range distances in proteins by multidimensional 13C-19F REDOR NMR under fast magic-angle spinning. J Biomol NMR 71:31-43
Mandala, Venkata S; Williams, Jonathan K; Hong, Mei (2018) Structure and Dynamics of Membrane Proteins from Solid-State NMR. Annu Rev Biophys 47:201-222
Liao, Shu Y; Lee, Myungwoon; Hong, Mei (2018) Interplay between membrane curvature and protein conformational equilibrium investigated by solid-state NMR. J Struct Biol :
Wang, Tuo; Jo, Hyunil; DeGrado, William F et al. (2017) Water Distribution, Dynamics, and Interactions with Alzheimer's ?-Amyloid Fibrils Investigated by Solid-State NMR. J Am Chem Soc 139:6242-6252
Lee, Myungwoon; Wang, Tuo; Makhlynets, Olga V et al. (2017) Zinc-binding structure of a catalytic amyloid from solid-state NMR. Proc Natl Acad Sci U S A 114:6191-6196
Fritzsching, Keith J; Hong, Mei; Schmidt-Rohr, Klaus (2016) Conformationally selective multidimensional chemical shift ranges in proteins from a PACSY database purged using intrinsic quality criteria. J Biomol NMR 64:115-30

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