Polypeptides Capable of Forming Homo-Oligomers with Modular Hydrogen Bond Network-Mediated Specificity and Their Design

Abstract

Methods and apparatus for identifying and screening hydrogen bond networks are provided. A computing device can determine a search space for hydrogen bond networks related to one or more molecules, where the search space can include a plurality of energy terms related to a plurality of residues related to the hydrogen bond networks. The computing device can search the search space to identify one or more hydrogen bond networks based on the plurality of energy terms. The computing device can screen the identified hydrogen bond networks to identity one or more screened hydrogen bond networks based on scores for the identified hydrogen bond networks. An output can be generated that is related to the one or more screened hydrogen bond networks. Also provided are polypeptides that can form homo-oligomers with modular hydrogen bond network-mediated specificity.

1 . A method, comprising:
 determining a search space for hydrogen bond networks related to one or more molecules using a computing device, wherein the search space comprises a plurality of energy terms related to a plurality of residues related to the hydrogen bond networks;   searching the search space to identify one or more hydrogen bond networks based on the plurality of energy terms using the computing device;   screening the identified one or more hydrogen bond networks to identify one or more screened hydrogen bond networks based on scores for the one or more identified hydrogen bond networks using the computing device; and   generating an output related to the one or more screened hydrogen bond networks.   
     
     
         2 . The method of  claim 1 , wherein the search space is configured as a graph having a plurality of nodes connected by one or more edges, wherein a node of the plurality of nodes is based on a particular residue of the plurality of residues, the particular residue having a residue position, and wherein an edge of the one or more edges connects a first node and a second node of the plurality of nodes based on a possible interaction between the first and second nodes. 
     
     
         3 . The method of  claim 2 , wherein the first node relates to a first residue of the plurality of residues, wherein the second node relates to a second residue of the plurality of residues, and wherein the possible interaction between first and second nodes relate to a possible interaction between a rotamer of the first residue and/or a rotamer of the second residue. 
     
     
         4 . The method of  claim 3 , wherein the possible interaction between the possible interaction between first and second nodes relates to an interaction energy between the first residue and the second residue. 
     
     
         5 . The method of  claim 4 , wherein determining the search space comprises:
 determining whether the interaction energy between the first residue and the second residue is less than a threshold interaction energy; and   after determining that the interaction energy between the first residue and the second residue is less than the threshold interaction energy, adding a hydrogen bond network comprising the first node, the second node, and at least one edge between the first and second nodes to the search space.   
     
     
         6 . The method of  claim 5 , wherein the at least one edge between the first and second nodes comprises information about the interaction energy between the first residue and the second residue. 
     
     
         7 . The method of  claim 6 , wherein the information about the interaction energy between the first residue and the second residue comprises a plurality of interaction energy values, wherein each interaction energy value in the plurality of interaction energy values is associated with a particular rotamer of the first residue and a particular rotamer of the second residue. 
     
     
         8 . The method of  claim 1 , wherein determining the search space comprises:
 determining at least a first residue position and a second residue position at an intermolecular interface between a first molecule and a second molecule, the first residue position associated with a first residue of the first molecule and the second residue position associated with a second residue of the second molecule; and   determining the search space based on the at least the first residue position and the second residue position.   
     
     
         9 . The method of  claim 8 , wherein at least one of the first molecule and the second molecule comprises a polypeptide chain. 
     
     
         10 . The method of  claim 1 , wherein searching the search space comprises searching all of the search space. 
     
     
         11 . The method of  claim 10 , wherein searching all of the search space comprises searching all of the search space using the depth-first search, or wherein searching all of the search space comprises searching all of the search space using a breadth-first search. 
     
     
         12 . (canceled) 
     
     
         13 . The method of  claim 1 , wherein searching the search space comprises:
 performing a first search of the search space to identify one or more initial hydrogen bond networks; and   identifying the one or more identified hydrogen bond networks by at least merging a first hydrogen bond network and a second hydrogen bond network of the one or more initial hydrogen bond networks   
     
     
         14 . The method of  claim 13 , wherein merging the first hydrogen bond network and the second hydrogen bond network comprises:
 determining whether the first hydrogen bond network and the second hydrogen bond network share an identical rotamer; and   after determining that the first hydrogen bond network and the second hydrogen bond network share an identical rotamer, merging the first hydrogen bond network and the second hydrogen bond network.   
     
     
         15 . The method of  claim 1 , wherein a particular score for a particular identified hydrogen bond network of the one or more identified hydrogen bond networks is based on a number of polar atoms that participate in the particular hydrogen bond network. 
     
     
         16 . The method of  claim 1 , wherein a particular score for a particular identified hydrogen bond network of the one or more identified hydrogen bond networks is based on a background reference structure. 
     
     
         17 . The method of  claim 16 , wherein the particular score for the particular identified hydrogen bond network is based on a score related to one or more sidechain-backbone hydrogen bonds, and wherein the one or more sidechain-backbone hydrogen bonds are related to the background reference structure. 
     
     
         18 . The method of  claim 1 , wherein a particular score for a particular identified hydrogen bond network of the one or more identified hydrogen bond networks is based on an energy function. 
     
     
         19 . The method of  claim 1 , wherein generating the output related to the one or more screened hydrogen bond networks comprises designing one or more molecules based on the screened hydrogen bond networks. 
     
     
         20 . (canceled) 
     
     
         21 . The method of  claim 1 , wherein generating the output related to the one or more screened hydrogen bond networks comprises generating a plurality of outputs related to the one or more screened hydrogen bond networks. 
     
     
         22 . The method of  claim 1 , wherein generating the output related to the one or more screened hydrogen bond networks comprises
 generating a synthetic gene that is based on the one or more screened hydrogen bond networks;   expressing a particular protein in vivo using the synthetic gene; and   purifying the particular protein.   
     
     
         23 . (canceled) 
     
     
         24 . A computing device, comprising:
 one or more data processors; and   a computer-readable medium, configured to store at least computer-readable instructions that, when executed, cause the computing device to perform the method of  claim 1 .   
     
     
         25 . (canceled) 
     
     
         26 . A computer-readable medium, configured to store at least computer-readable instructions that, when executed by one or more processors of a computing device, cause the computing device to perform the method of  claim 1 . 
     
     
         27 - 49 . (canceled)