Evolving new molecular function

Abstract

Nature evolves biological molecules such as proteins through iterated rounds of diversification, selection, and amplification. The present invention provides methods, compositions, and systems for synthesizing, selecting, amplifying, and evolving non-natural molecules based on nucleic acid templates. The sequence of a nucleic acid template is used to direct the synthesis of non-natural molecules such as unnatural polymers and small molecules. Using this method combinatorial libraries of these molecules can be prepared and screened. Upon selection of a molecule, its encoding nucleic acid template may be amplified and/or evolved to yield the same molecule or related molecules for re-screening. The inventive methods and compositions of the present invention allow for the amplification and evolution of non-natural molecules in a manner analogous to the amplification of natural biopolymer such as polynucleotides and protein.

1 . A method of synthesizing one or more chemical compounds, the method comprising the steps of:
 providing one or more templates, which one or more templates optionally have a reactive unit associated therewith;   contacting one or more transfer units having an anti-codon and reactive unit with said one or more templates under conditions to allow for hybridization of the one or more anti-codons to the template, and reaction of the reactive units.   
     
     
         2 .- 46 . (canceled) 
     
     
         47 . A library of chemical compounds, the library comprising oligonucleotide templates covalently attached to macrocyclic peptides comprising a macrocyclic ring comprising four amino acids and three peptide bonds, wherein the amino acids optionally comprise a non-proteinogenic side chain and the macrocyclic ring is cyclized through a side chain of one of the amino acids, and
 wherein each oligonucleotide has a nucleotide sequence informative of the synthetic history of the macrocyclic peptide covalently attached therewith.   
     
     
         48 . The library of  claim 47 , wherein each macrocyclic ring comprises 14 ring atoms.