Proteins play critical roles in imparting the unique physical properties in mammalian lung surfactant. Failure to express functional surfactant protein B, SP-B, is lethal, and application of exogenous lung surfactant has proved beneficial in treating some respiratory distress syndromes. However, success or failure of various lung surfactant preparations in treating specific individuals is unpredictable, and a solid understanding of the molecular basis for the role of SP-B in lung surfactant is lacking. Understanding the complex interactions between SP-B and the lipids present in lung surfactant could direct the formulation of clinical surfactant preparations for specific diseases including adult respiratory distress syndrome (ARDS), severe acute respiratory syndrome (SARS), respiratory distress syndrome (RDS) in premature infants, and meconium aspiration. Determining the structure and mechanisms of action for smaller peptide analogs of SP-B would aid in the development of low-cost, synthetic replacement therapies which could replace animal-derived formulations. We propose to study the function of SP-B under physiologically relevant conditions and to determine whether peptide analogs of the N- and C- terminus of SP-B can adopt stable complexes with lipids which mimic the actions of the parent protein. Studying the structure, orientation, and locations of these peptides in bilayer membranes will aid in determining under what conditions they can serve as replacements for the full protein. We will be using novel, sensitive solid state NMR experiments which allow us to determine at atomic resolution these parameters at low concentrations in complex lipid environments.
|Frederick, Thomas E; Goff, Philip C; Mair, Chad E et al. (2010) Effects of the endosomal lipid bis(monoacylglycero)phosphate on the thermotropic properties of DPPC: A 2H NMR and spin label EPR study. Chem Phys Lipids 163:703-11|
|Long, Joanna R; Mills, Frank D; Ganesh, Omjoy K et al. (2010) Partitioning, dynamics, and orientation of lung surfactant peptide KL(4) in phospholipid bilayers. Biochim Biophys Acta 1798:216-22|
|Farver, R Suzanne; Mills, Frank D; Antharam, Vijay C et al. (2010) Lipid polymorphism induced by surfactant peptide SP-B(1-25). Biophys J 99:1773-82|
|Antharam, Vijay C; Elliott, Douglas W; Mills, Frank D et al. (2009) Penetration depth of surfactant peptide KL4 into membranes is determined by fatty acid saturation. Biophys J 96:4085-98|
|McNeill, Seth A; Gor'kov, Peter L; Shetty, Kiran et al. (2009) A low-E magic angle spinning probe for biological solid state NMR at 750 MHz. J Magn Reson 197:135-44|
|Mills, Frank D; Antharam, Vijay C; Ganesh, Omjoy K et al. (2008) The helical structure of surfactant peptide KL4 when bound to POPC: POPG lipid vesicles. Biochemistry 47:8292-300|
|Antharam, Vijay C; Farver, R Suzanne; Kuznetsova, Anna et al. (2008) Interactions of the C-terminus of lung surfactant protein B with lipid bilayers are modulated by acyl chain saturation. Biochim Biophys Acta 1778:2544-54|