What are the structural features that allow RNA molecules to catalyze chemical transformations?

We will use a combination of X-ray crystallography, biochemistry, and computational enzymology to unravel the mechanisms of catalytic RNAs or ribozymes - both found in nature and artificially evolved in the laboratory. 

How do RNA molecules acquire new catalytic structures and functions?

We will use a combination of evolutionary and computational approaches, informed by molecular design principles to explore RNA mutational fitness landscapes to identify evolutionarily feasible pathways between distinct RNA enzymes. The preponderance of 'neutral' mutational pathways will indicate that distinct structures and functions may be easily accessed through mutational drifts across the RNA sequence space.

How are RNA function and evolution influenced by prebiotic environments?

We will use laboratory evolution, bioinformatics, and high-throughput structure probing to map the sequence and structural landscapes of RNA molecules as they evolve under various selection pressures that simulate prebiotically relevant crowded and confined environments. These include the presence of amino acids, peptides, sugars, nucleosides, minerals, temperature, and pH fluctuations, and inside different cell-like compartments.

How did the earliest cells behave?

All life is cellular. To better understand how primordial life may have emerged in a prebiotic milieu, we will build models of primordial cells or protocells with molecules presumed to be present on early Earth. Our system of interest is a protocell bounded by a fatty acid membrane encapsulating RNA enzymes within. We aim to establish RNA-catalyzed genome replication and metabolic reactions relevant to primordial biology inside these protocells, with the ultimate goal of triggering Darwinian evolution in them.