Structure-sequence based analysis for identification of conserved regions in proteins

1. A computer-implemented method of scoring a set of residues within a cluster of proteins from an initial set of three dimensional protein structures, comprising:

identifying, by a computer, the initial set of three dimensional protein structures, each comprising a polypeptide sequence and structural coordinates;

generating, by the computer, a plurality of pair-wise protein structure alignments of the set of three dimensional protein structures;

for each pair of protein structures in the set:

generating, by the computer, a first plurality of fragments from a first protein structure in the pair and a second plurality of fragments from a second protein structure in the pair, wherein each fragment is a polypeptide sequence of contiguous residues of a pre-determined length and has associated distances of structural coordinates of contiguous residue pairs;

identifying, by the computer, a plurality of contiguous residue pairs from the first plurality of fragments and the second plurality of fragments having structural coordinates within the first pre-determined distance and having a pre-determined length, thereby identifying a plurality of pair-wise candidate spans for the pair;

determining, by the computer, a pair-wise local similarity value that indicates the number of first plurality of fragments and second plurality of fragments that share candidate spans;

determining, by the computer, a pair-wise global similarity value that indicates a number of residues that form a plurality of residue pairs from the first protein structure and the second protein structure, wherein a structural coordinate of each member of the residue pair falls within a second pre-determined distance based on the pair-wise structural alignment;

generating, by the computer, a cluster of protein structures from the initial set of protein structures using the identified pair-wise candidate spans, the pair-wise local similarity values, and the pair-wise global similarity values;

aligning, by the computer, all protein structures in the cluster to generate a one-to-one residue correspondence of the residue pairs for the cluster of protein structures;

identifying, by the computer, a span from the cluster of protein structures, wherein each span comprises a set of one-to-one correspondences of residues that are within the first pre-determined distance of each other and within the second pre-determined distance based on the plurality of pair-wise structural alignments of the cluster of protein structures;

generating, by the computer, a plurality of conservation scores for the cluster of protein structures, wherein the conservation scores are calculated for a plurality of residues within the span based on a metric for residue similarity; and

storing, by the computer, the plurality of conservation scores, thereby scoring the set of residues within the cluster of protein structures.

2. The method of claim 1 , wherein the first pre-determined distance is less than 0.5 Angstroms.

3. The method of claim 1 , wherein the second pre-determined distance is less than 5.0 Angstroms.

4. The method of claim 1 , wherein the span comprises 3 or more contiguous residues.

5. The method of claim 1 , wherein 3 or more conservation scores are generated and stored.

6. The method of claim 5 , further comprising selecting, by the computer, a subset of high-scoring residues based on the plurality of conservation scores.

7. The method of claim 1 , further comprising displaying, by the computer, a first conservation score of the plurality of conservation scores with a representation of a selected protein structure of the cluster of protein structures.

8. The method of claim 7 , wherein the representation is a three-dimensional representation of a selected protein structure of the cluster of protein structures.

9. The method of claim 7 , wherein the representation is a representation of an alignment comprising the selected protein structure of the cluster of protein structures.

10. The method of claim 1 , further comprising displaying, by the computer, said conservation scores with a linear representation of a selected protein structure of the cluster of protein structures.

11. The method of claim 1 , wherein the plurality of protein structures comprises a structure obtained using x-ray crystallography, electron microscopy, nuclear magnetic resonance spectroscopy, computational protein structure modeling, or a combination thereof.

12. The method of claim 1 , wherein the metric for residue similarity incorporates information about residue identity, residue non-identity and residue class, information defined by a substitution matrix or a combination thereof.

13. A computer-readable non-transitory storage medium comprising program code for scoring a set of residues within a cluster of proteins from an initial set of three dimensional protein structures, the program code comprising program code for:

identifying, by a computer, the initial set of three dimensional protein structures, each comprising a polypeptide sequence and structural coordinates;

generating, by the computer, a plurality of pair-wise protein structure alignments of the set of three dimensional protein structures;

for each pair of protein structures in the set:

generating, by the computer, a first plurality of fragments from a first protein structure in the pair and a second plurality of fragments from a second protein structure in the pair, wherein each fragment is a polypeptide sequence of contiguous residues of a pre-determined length and has associated distances of structural coordinates of contiguous residue pairs;

identifying, by the computer, a plurality of contiguous residue pairs from the first plurality of fragments and the second plurality of fragments having structural coordinates within the first pre-determined distance and having a pre-determined length, thereby identifying a plurality of pair-wise candidate spans for the pair;

determining, by the computer, a pair-wise local similarity value that indicates the number of first plurality of fragments and second plurality of fragments that share candidate spans;

determining, by the computer, a pair-wise global similarity value that indicates a number of residues that form a plurality of residue pairs from the first protein structure and the second protein structure, wherein a structural coordinate of each member of the residue pair falls within a second pre-determined distance based on the pair-wise structural alignment;

generating, by the computer, a cluster of protein structures from the initial set of protein structures using the identified pair-wise candidate spans, the pair-wise local similarity values, and the pair-wise global similarity values;

aligning, by the computer, all protein structures in the cluster to generate a one-to-one residue correspondence of the residue pairs for the cluster of protein structures;

identifying, by the computer, a span from the cluster of protein structures, wherein each span comprises a set of one-to-one correspondences of residues that are within the first pre-determined distance of each other and within the second pre-determined distance based on the plurality of pair-wise structural alignments of the cluster of protein structures;

generating, by the computer, a plurality of conservation scores for the cluster of protein structures, wherein the conservation scores are calculated for a plurality of residues within the span based on a metric for residue similarity; and

storing, by the computer, the plurality of conservation scores, thereby scoring the set of residues within the cluster of protein structures.

14. The computer-readable storage medium of claim 13 , further comprising displaying a first conservation score of the plurality of conservation scores with a representation of a selected protein structure of the cluster of protein structures.

15. The computer-readable storage medium of claim 13 , wherein the metric for residue similarity incorporates information about residue identity, residue non-identity and residue class, information defined by a substitution matrix or a combination thereof.