I have been working on two projects, as most members of our group are, and these are summarized in the following sections:
Project I:
Enzyme-DNA-Inorganic NanoMaterials
Enzymes
are highly specific and efficient catalysts with superb regio-, chemo- and stereoselectivities. However, the common use of these
wonderful catalysts, in the laboratory, is severely restricted due to their
exorbitant price, poor stability and high sensitivity to pH/temperature. Some
of the above limitations of enzymes can be readily overcome by the
encapsulation of the biocatalysts in solid inorganic materials. Our group has pioneered the use of
transition metal phosphates (cartoon above, where the blue spheres represent
proteins, intercalated between two layers of the inorganic framework of metal
and phosphate groups). The metal
phosphate lattice is negatively charged, and proteins with a formal positive
charge bind to these solids avidly.
Bound proteins and enzymes exhibited improved properties when compared
to those of the corresponding biocatalysts in solution. For example, the catalytic activities
as well as selectivities are improved by intercalating the biocatalysts in the
solids.
Recently, we discovered that co-intercalation of double helical DNA in these galleries improves the properties of the intercalated biocatalysts even further. 1,2 The metal phosphate lattice in the above solids can be readily replaced by layered double hydroxides where the inorganic matrix can carry a net positive charge. Therefore, these materials are suitable for the intercalation of proteins and enzymes which sport a net negative charge.
Novel bionanomaterials consisting of enzymes, DNA and inorganic solids are providing new avenues for protein formulations, biocatalysis and gene delivery. Improving the properties of the biocatalysts is my long term goal.
Project
II: Dynamic Molecular Evolution Ð
New Approach for the Synthesis of High Affinity Ligands for Selected Targets
Rational design of high affinity ligands to specific biological targets is a challenging. Successful achievement of this task could result in revolutionary cancer therapies and high sensitivity dagnostic methods. In a majority of these situations the structure of the binding site is unknown. Revolutionary approaches are being designed in our group to meet this challenge. Traditional methods used for this purpose consist of either a combinatorial approach or a structure-based design. In the former, thousands of compounds are screened to obtain a lead and then structure-activity studies are carried out to optimize the activity of the ligand. On the other hand, the later approach requires a good knowledge about the active site structure, which is often not the case. Both these approaches are quite laborious, time-consuming, and expensive. Our novel approach exploits dynamic equilibrium conditions to evolve molecular structure in the desired direction, in real time. Similar to a set of legos used to construct desired structures, we are using simple building blocks to prepare a large population of diverse structures (M1, M2, M3É) which are in dynamic equilibrium. The desired, active component (M3) is selectively enriched from this diverse population by target-training. Preliminary studies are underway to test this radically different approach for the synthesis of new leads.
