Determining the functions and interactions of proteins by comparative analysis

The method of claim 1 or claim 2, wherein the drug is an anti-microbial drug.

The method of claim 1 or claim 2, wherein the first nucleic acid or a polypeptide sequence is derived from a pathogen.

The method of claim 4, wherein the pathogen is a microorganism.

The method of claim 1 or claim 2, wherein the microorganism is Mycobacterium tuberculosis (MTB).

The method of claim 1 or claim 2, wherein the plurality of sequences used to identify a second sequence comprises a database of the gene sequences of an entire genome of an organism.

The method of claim 1 or claim 2, wherein the plurality of sequences used to identify a second sequence comprises a database of the gene sequences derived from a pathogen.

The method of claim 9, wherein the phylogenetic profile is in the form of a vector, matrix or phylogenetic tree.

The method of claim 9, comprising determining the significance of homology between the proteins by computing a probability (p) value threshold.

The method of claim 11, wherein the probability is set with respect to the value 1/NM, based on the total number of sequence comparisons that are to be performed, wherein N is the number of proteins in the first organism"s genome and M in all other genomes.

The method of claim 9, wherein the presence or absence is by calculating an evolutionary distance.

The method of claim 14, wherein the conditional probability matrix is defined by a Markov process with substitution rates, over a fixed time interval.

The method of claim 14, where the conversion from an amino acid substitution matrix to a conditional probability matrix is represented by:

• 10 P B ⁢ ( i → j ) = p ⁢ ( j ) ⁢ 2 ⁢ ⋀ ⁢ B ⁢ ⁢ L ⁢ ⁢ O ⁢ ⁢ S ⁢ ⁢ U ⁢ ⁢ M62 ij 2 , ,
• where BLOSUM62 is an amino acid substitution matrix, and P(i→j) is the probability that amino acid i is replaced by amino acid j through point mutations according to BLOSUM62 scores.

The method of claim 16, where Pj"s are the abundances of amino acid j and are computed by solving a plurality of linear equations given by the normalization condition that:

• 11 ∑ i ⁢ P B ⁢ ( i → j ) = 1

The method of claim 1 or claim 2, wherein the "physiologic linkage"method algorithm identifies proteins and nucleic acids that participate in a common functional pathway.

The method of claim 1 or claim 2, wherein the "physiologic linkage"method algorithm comprises identifies proteins and nucleic acids that participate in the synthesis of a common structural complex.

The method of claim 1 or claim 2, wherein the "physiologic linkage"method algorithm comprises identifies proteins and nucleic acids that participate in a common metabolic pathway.

The method of claim 1 or claim 2, wherein the "domain fusion"method algorithm comprises

• (a) aligning a first primary amino acid sequence of multiple distinct non-homologous polypeptides to second primary amino acid sequence of a plurality of proteins;
• and
• (b) for any alignment found between the first primary amino acid sequences of all of such multiple distinct non-homologous polypeptides and at least one protein of the second primary amino acid sequences, outputting an indication identifying the aligned second primary amino acid sequence as an indication of a functional link between the aligned first and second polypeptide sequences.

The method of claim 21, wherein the aligning is performed by an algorithm selected from the group consisting of a Smith-Waterman algorithm, Needleman-Wunsch algorithm, a BLAST algorithm, a FASTA algorithm, and a PSI-BLAST algorithm.

The method of claim 21, wherein the multiple distinct non-homologous polypeptides are obtained by translating a nucleic acid sequence from a genome database.

The method of claim 21, wherein the plurality of proteins have a known function.

The method of claim 21, wherein at least one of the multiple distinct non-homologous polypeptides has a known function.

The method of claim 21, wherein at least one of the multiple distinct non-homologous polypeptides has an unknown function.

The method of claim 21, wherein the alignment is based on the degree of homology of the multiple distinct non-homologous polypeptides to the plurality of proteins.

The method of claim 21, further comprising determining the significance of the aligned and identified second primary amino acid sequence by computing a probability (p) value threshold.

The method of claim 28, wherein the probability threshold is set with respect to the value 1/NM, based on the total number of sequence comparisons that are to be performed, wherein N is the number of proteins in a first organism"s genome and M in all other genomes.

The method of claim 21, further comprising filtering excessive functional links between one first primary amino acid sequence of multiple distinct non-homologous polypeptides and an excessive number of other distinct non-homologous polypeptides for any alignment found between the first primary amino acid sequences of the distinct non-homologous polypeptides and at least one of the second primary amino acid sequences of the plurality of proteins.

A computer system, comprising:

• (a) a processor;
• and
• (b)a computer program product as set forth in claim 31 or claim 32.