Ayyalusamy (Rams) Ramamoorthy

Membrane proteins act as enzymes, regulate transport processes, and play a central role in intercellular communication. In order to understand the diverse functions of membrane proteins and to engineer these functions for biomedical or biotechnological purposes, it is necessary to determine their high-resolution structure and to describe their dynamics. My research group focuses on the investigation of atomistic resolution dynamic structures of membrane associated proteins and protein-protein complexes, and understanding the role of membrane composition on protein folding, misfolding and aging related diseases. 

The development of NMR methods and their applications to determine the structure and describe the dynamics of membrane associated proteins and amyloid proteins are the main goals of the research program. Biology of the research program involves the preparation of peptides and proteins associated with membranes through synthetic or molecular biological methods. All aspects of sample preparation are optimized including the incorporation of specific and selective isotopic labels, isolation, purification, and final preparation of NMR samples. Cytochrome P450, cytochrome P450 reductase, cytochrome b5, and amyloid proeins (including amyloid-beta and islet amyloid polypeptide (IAPP or amylin)) are some of the systems currently under investigation by our group. Solid-state NMR experiments on membrane proteins incorporated in oriented and unoriented lipid bilayers and solution NMR experiments on membrane proteins in nanodiscs or lipid bicelles are performed to determine the dynamic structures of membrane proteins and protein-proein complexes.

Solid-state NMR spectroscopy is one of the premier methods for studying the structure and dynamics of molecules in solids. Ramamoorthy's research program orchestrates the theoretical design, experimental demonstration, and application of new and cutting edge solid-state NMR spectroscopic methods to study the structure and properties of molecules in single crystalline, liquid crystalline, polycrystalline, and amorphous phases. The design of solid-state NMR methods is composed of a variety of sophisticated techniques including specifically constructed multiple radio-frequency pulses, magic-angle spinning, multiple resonance schemes, sensitivity enhancement procedures, selective observation or hybridization of them. This basic research on spin physics encompasses theoretical and experimental aspects of spin engineering, computer simulations, and instrumentation.

Some of the ongoing projects are: 

1. Solving atomistic resolution dynamic structure of ~72-kDa cytochromes-P450-b5 complex and >130-kDa cytochromes-P450-CYPOR complex using nanodiscs and a combination of solution and solid-state NMR techniques to fully understand the enzymatic function of cytochrome-P450. 

2. Roles of structure, dynamics, and membrane interaction of cytochrome-P450 on its ability to oxidize a variety of drugs. 

3. Investigation of an amyloid protein aggregation at the membrane interface using model membranes (liposomes or nanodiscs) and a combination of biophysical and cbiochemical approaches. 

4. Development of multidimensional solid-state NMR techniques to enhance spectral resolution and sensitivity. 

5. Solid-state NMR investigation of bone materials, polymorphic pharmaceuticals and nanomaterials. 

Representative Publications:

Zhang M, Huang R, Ackermann R, Im SC, Waskell L, Schwendeman A, Ramamoorthy A. Reconstitution of the Cytb5-CytP450 Complex in Nanodiscs for Structural Studies Using NMR Spectrsocopy. Angew. Chem. Int. Ed. Eng. 55 (2016) 44974499.

Korshavn KJ, Bhunia A, Lim MH, Ramamoorthy A. Amyloid-Beta Adopts a Conserved, Partially Folded Structure upon Binding to Zwitterionic Lipid Bilayers Prior to Amyloid Formation. Chem. Commun. 52 (2016) 882-885. 

Pandey MK, et al. 1020 MHz single-channel proton fast magic angle spinning solid-state NMR spectroscopy. J. Magn. Reson. 261 (2015) 1-5. 

Zhang M, Huang R, Im SC, Waskell L, Ramamoorthy A. Effects of membrane mimetics on cytochrome P450-cytochrome b5 interactions characterized by NMR spectroscopy. J. Biol. Chem. 290 (2015) 12705-12718. 

Huang R, Zhang M, Rwere F, Waskell L, Ramamoorthy A. Kinetic and structural characterization of the intraction between the FMN binding domain of Cytochrome P450 reductase and cytochrome c. J. Biol. Chem. 290 (2015) 4843-4855. 

Kotler SA, Walsh P, Brender JR, Ramamoorthy A. Differences between amyloid-beta aggregation in solution and on the membrane: Insights in to elucidation of the mechanistic details of Alzheimer's disease. Chem. Soc. Rev. 43 (2014) 6692-6700. 

Research Areas(s)

• Bioanalytical Chemistry
• Bioinorganic Chemistry
• Chemical Biology
• Materials Chemistry
• Nano Chemistry
• Physical Chemistry
• NMR Spectroscopy
• Structural Biology of Membrane Proteins and Amyloid Proteins

Awards

• Hans Fischer Senior Fellow, Technical University of Munich, 2015
• Rackham Faculty Recognition Award, 2012
• American Association for the Advancement of Science Fellow, 2009
• Japan Society for the Promotion of Science Fellow, 2009
• Willsmore Fellow, University of Melbourne, Australia, 2009
• NSF Career Development Award 

Fellowships

• American Association for the Advancement of Science Fellow, 2009
• Japan Society for the Promotion of Science Fellow, 2009
• Willsmore Fellow, University of Melbourne, Australia, 2009

Other Postions

• Distinguished Visiting Professor, Osaka University
• Visiting Scientist, Max Planck Institute, Mainz, Germany