Abstract: This disclosure describes processes that permit a scientist to generate experimentally testable hypotheses concerning the function of a protein starting from an evolutionary analysis. This begins with a process to determine relative and absolute dates of events in the molecular record by examining exchanges involving transitions at silent sites in two or more DNA sequences. A process is then disclosed for determining, for a specific lineage, features of the divergent evolution of the protein family. Processes are then disclosed that use these as tools to identify, at the level of hypothesis, protein pairs that are functionally linked, including functional interactions in pathways and regulatory networks. Processes are then disclosed that use these tools to correlate events recorded in the molecular sequence record with events recorded in the paleontological and geological records, permitting the association of genes with preselected physiologies in higher organisms.

Abstract: Improvements are disclosed for in vitro selection methods that yield ligands and catalysts through partitioning libraries of oligonucleotides. These improvements all increase the diversity and amount of fuctionality available to the oligonucleotides, by incorporating into the oligonucleotide libraries non-standard nucleobase analogs and/or functionalized standard nucleobases, and/or incorporating into the selection mixture organic cofactors that deliver functional groups by binding non-covalently to oligonucleotides in the library.

Abstract: The disclosure describes building blocks for preparing oligonucleotides carrying non-standard nucleobases that can pair with complementary non-standard nucleobases so as to fit the Watson-Crick geometry, in that the resulting base pair joins a monocyclic six membered ring pairing with a fused bicyclic heterocyclic ring system composed of a five member ring fused with a six membered ring, with the orientation of the heterocycles with respect to each other and with respect to the backbone chain analogous to that found in DNA and RNA, but with a pattern of hydrogen bonds holding the base pair together different from that found in the AT and GC base pairs (a “non-standard base pair”).

Abstract: This invention dicloses compositions of matter that are oligonucleotide analogs containing one or more improvements, where the improvement consists of replacing one or more of the phosphodiester linking units (—O—PO2−—O—) by a dimethylene sulfide (—CH2—S—CH2—), sulfoxide (—CH2—SO—CH2—), or sulfone linking unit (—CH2—SO2—CH2—). This linkage is stable to degradation both by enzymes and by alkaline hydrolysis, contains no stereogenic atoms, and confers improved stability and the ability to fold into tertiary structure upon natural oligonucleotides and their analogs.

Abstract: A method for making a model for the folded structure of a set of proteins from an evolutionary analysis of a set of aligned homologous protein sequences was claimed in Ser. No. 07/857,224. The instant application concerns methods for using these models. The first method is used to confirm or deny a hypothesis that two proteins are homologous, and is comprised of comparing a predicted structure model for one family of proteins with a predicted structure model for a second family of proteins, or an experimental structure for the second family, and deducing the presence or absence of homology based on the presence or absence of structural similarity flanking key residue motifs in the polypeptide sequence.

Abstract: The disclosure describes building blocks for preparing oligonucleotides carrying non-standard nucleobases that can pair with complementary non-standard nucleobases so as to fit the Watson-Crick geometry, in that the resulting base pair joins a monocyclic six membered ring pairing with a fused bicyclic heterocyclic ring system composed of a five member ring fused with a six member ring, with the orientation of the heterocycles with respect to each other and with respect to the backbone chain analogous to that found in DNA and RNA, but with a pattern of hydrogen bonds holding the base pair together different from that found in the AT and GC base pairs (a "non-standard base pair").

Abstract: The disclosure describes a new method for intermolecular recognition between two molecules, where complementary oligonucleotide strands bind in aqueous solution, where these strains contain non-standard nucleobases that can pair to fit the Watson-Crick geometry in that they involve a monocyclic six membered ring pairing with a fused bicyclic heterocyclic ring system composed of a five member ring fused with a six membered ring, with the orientation of the heterocycles with respect to each other and with respect to the backbone chain analogous to that found in DNA and RNA, but with a pattern of hydrogen bonds holding the base pair together different from that found in the AT and GC base pairs (a "non-standard base pair").

Abstract: The disclosure describes new compositions of matter that are analogs of DNA and RNA containing heterocyclic bases that can form base pairs that fit the Watson-Crick geometry in that they involve a monocyclic six membered ring pairing with a fused bicyclic heterocyclic ring system composed of a five member ring fused with a six membered ring, with the orientation of the heterocycles with respect to each other and with respect to the backbone chain analogous to that found in DNA and RNA, but where these base pairs are joined by a pattern of hydrogen bonds different from that found in the AT and GC base pairs (a "non-standard base pair").

Abstract: Improvements are provided for methods for selecting in vitro compositions of matter that serve as ligands and catalysts. Also provided are novel nucleoside analogs that expand the structural diversity of oligonucleotides and their analogs.

Abstract: This invention provides a method for preparing molecules that bind to a preselected receptor, whereby the receptor itself acts as an agent for either joining two ligand fragments to form a composite, tight binding ligand, or selects a composite ligand from a mixture in solution where ligand fragments are being joined and unjoined reversibly under equilibrium conditions.

Abstract: A method is presented for predicting the folded structure of proteins that comprises obtaining an alignment of the sequences of a set of homologous proteins, using patterns of conservation and variation of the sequence between proteins with clearly defined evolutionary relationships to assign positions in the alignment to the surface of the folded structure, the inside of the folded structure, active site, or parsing segments, assigning secondary structures by identifying periodicity in said assignments, and then assembling the secondary structural units into a globular form using distance constraints imposed by disulfide bridges, active site assignments, and covariation analysis.