SCOL Project: Searching peptide sequence space for prebiotic aggregates and catalysts
Origins of life lie primarily in the complex processes that simple molecules began to perform millions of years ago. These processes form the precursors for most vital biological functions in our now-evolved biochemistry. The catalytic action of enzymes, reproduction of cells and replication of our genetic matter — all of these vital processes — are believed to have simple origins. Recent papers suggest that short peptides can have a vital role to play in all of these processes from an origins-of-life perspective. However, from the huge library of peptide sequences that are possible, only a very small percentage has been screened for their utility in assisting the simple chemical precursor processes. This has been due to the fact that the only available alternative currently is the manual screening of a sequence, which is, of course, an arduous task.
We in this proposal try to alleviate this problem by designing a dynamic (constantly exchanging) library of peptides that will be engineered to respond to various chemical selection steps. Through these steps, the library should enrich a suitable candidate for a chemical transformation on its own. Dimers of various combinations of amino acids would form the initial feed, and the library would be under constant rearrangement for choosing the best combination out of these amino acids until it converges to a major product of a suitable candidate. This approach is novel, as covalent bonds between amino acids that form peptides are known to be inherently non-dynamic and, in the past, have been difficult to manipulate. Our approach uses the reversible enzymatic hydrolysis of this covalent bond to its advantage by converging the library to a suitable candidate. This candidate can further be isolated and tested independently for its efficacy in performing the desired chemical transformation. It should be noted that the feed of amino acid dimers will only consist of amino acids relevant to prebiotic chemistry so that the final product obtained can be used for relevant prebiotic investigations. Since the peptides are in dynamic exchange, the convergence of such a library can be affected by various screening steps.
In this proposal, we have chosen specific strategies so the screening can be suited for peptide catalysts that can either act as prebiotic enzyme mimics or can facilitate auto-reproduction of lipid vesicles or can act as binders for RNA and facilitate its non-enzymatic replication. Thus, from a common strategy, suitable peptide candidates can be selected by simply varying the screening steps. We believe that this approach would not only allow screening of a large portion of available prebiotic peptide sequence space, but will also serve as a common platform upon which prebiotic peptides relevant to important questions on origins of life — such as enzyme mimics, self-reproduction of lipid vesicles and non-enzymatic replication of RNA — can be developed.
Education: Jawaharlal Nehru Centre for Advanced Scientific Research, Ph.D., Supramolecular Chemistry
Institution: Research Foundation of CUNY on behalf of Advanced Science Research Center (laboratory of Rein Ulijn)