Research Interest
1. Novel amphiphile development for membrane protein research
Despite considerable progress in the development of new compounds and strategies for membrane protein solubilization and stabilization, new tools are needed, because many IMPs are currently refractory. Given the great variation in structure and physical properties among membrane proteins, it is very unlikely that a single amphiphile or amphiphile family will be optimal for every system, or even most systems, and exploration of new amphiphilic agents is therefore important for membrane protein biochemistry.
Our lab has developed several kinds of novel amphiphiles widely used for membrane protein study including tripod amphiphiles (TPAs), tandem facial amphiphiles (TFAs), MNG amphiphiles (MNGs), GNG amphiphiles (GNGs) and glyco-diosgenin amphiphile (GDN). Among these agents, GNG amphiphiles are particularly promising for X-ray crystallography-based membrane protein studies. MNG amphiphiles have proven their worth by enabling the acquisition of several G-protein coupled receptor (GPCR) crystal structures. Using MNG-3 (LMNG), membrane protein scientists have generated more than high resolution structures of 145 GPCRs and 157 non-GPCRs (channels, transporters, etc.). GDN is widely used for cryoEM-based protein structural study and has been used for structural studies of 196 membrane proteins. With collaborations with Bernadette Byrne (Imperial College London, UK), Lan Guan (Texas Tech., US), Claus Loland (Copenhagen Univ., Denmark), Brian Kobilka (Stanford Univ., USA), we are continuing the development of novel amphiphiles. Recently our lab published four JACS (2016, 2017,2019, 2020; IF = 14.7) and five Chemical Science (2016, 2017, 2019,2022; IF = 9.7) papers individually introducing a class of new amphiphiles. As of March. 2022, more than 30 new detergents that were invented in our lab are commercialized from Anatrace or Avanti.
2. Micellar catalyst development
In 1970s, it was first observed that the presence of aqueous micellar solutions of ionic surfactants significantly enhanced the reaction rate of organic compounds, especially in the vicinity of the critical micelle concentration. On the other hand, for some reactions, however an opposite effect i.e. decrease in the reaction rate were noted, which named as micellar inhibition. Whereas the former was called micellar catalysis. Gradually interests in micellar catalysis arose among the scientific community, mainly due to its importance in biochemical applications as well as the huge time, material and energy that may be saved in this process. Many biochemical reactions in the living cell occur at interfaces like the active sites of an enzyme or other transmembranic proteins inside the lipid bilayer, therefore critically dependent on the local microenvironment, concentrations and relative orientations of the bound reactants. The realization that micelles can provide a realistic mimics of cell membrane give a major thrust in the investigations on micellar catalysis. We hypothesized that micellar catalysis could potentially provide dramatic increases in reaction rate and yield in amine-catalyzed reaction to synthesize a hetero diels-alder adduct. For this purpose we have designed and synthesized new amphiphilic catalysts, which carry the required recognition motifs in their catalytic sites. Investigations along these lines are currently underway in our laboratory.
3. Fluorescent chemo-sensor development
Chemosensory devices (chemosensors/chemodosimeters) transform the qualitative and/or quantitative information of an analyte present in the aqueous media (i.e. drinking or river or waste water or in the biological systems) to an optical signal (measurable absorbance or fluorescence change). The optical (both chromogenic and fluorescent) molecular probes possessing appropriate functionalities have consistently demonstrated their potential to analyze cations, anions and neutral species, both qualitatively and quantitatively. These detection methods are cost effective, rapid and facile and are applicable as analytical tools in environmental, medical, biochemical areas as well as in industry. In the present research program, it is planned to design and synthesize multipodal (di, tri, tetra, etc.) and cyclic molecular architectures possessing two or more amidic/positively charged moieties directed on appropriate platform like benzene, anthracene, pyrene, naphthalene, acridine, fluorescein, rhodamine, perylene, tren, bile acids etc. and explore their applications as photo-responsive chemosensors and chemodosimeters for recognition of biologically relevant analytes (e.g. anions, metal ions, and small neutral organic molecules) and hazardous materials (e.g. explosives i.e. 2,4,6-trinitrophenol, TNT, etc.). In addition to the synthesis of organic molecule-based sensors, we have also planned to synthesize hybrid inorganic-organic frameworks as molecular sensors because of their re-usability. Dr. Kumar is a leader of this project who has published several papers over the past a couple of years.
