Thermodynamic measures on protein-protein interaction networks for cancer therapy

Abstract

A method to select a protein target for therapeutic application includes accessing genomic information and protein-protein interaction (PPI) data, computing a thermodynamic measure for each protein node within the network of protein nodes, generating an energy landscape data corresponding to the network of protein nodes and the thermodynamic measure, generating a PPI subnetwork by applying a topological filtration to the energy landscape data of the PPI data, computing a first Betti number for the PPI subnetwork, sequentially removing a protein node(s) from the PPI subnetwork while replacing the previously removed nodes(s), computing a new Betti number for the PPI subnetwork with the protein node(s) removed, computing a change between the Betti numbers, and determining, based on the change between the Beti numbers, a most significant protein target within the PPI network.

What is claimed is: 
     
         1 . A method to select a protein target for therapeutic application, comprising:
 accessing genomic information and protein-protein interaction (PPI) data, the PPI data comprising a network of protein nodes from at least one source;   computing, using the genomic information and the PPI data, a thermodynamic measure for each protein node within the network of protein nodes;   generating an energy landscape data corresponding to the network of protein nodes and the thermodynamic measure;   generating a PPI subnetwork by applying a topological filtration to the energy landscape data of the PPI data;   computing a first Betti number for the PPI subnetwork;   sequentially removing a first protein node from the PPI subnetwork;   computing a second Betti number for the PPI subnetwork with the first protein node removed;   computing a change between the first Betti number and the second Betti number;   replacing the first protein node into the PPI subnetwork;   sequentially removing a second protein node from the PPI subnetwork, wherein the second protein node is different from the first protein node;   computing a third Betti number for the PPI subnetwork with the second protein node removed and the first protein node replaced;   computing a change between the first Betti number and the third Betti number;   determining, based on the change between the first Betti number and the second Betti number and the change between the first Betti number and the third Betti number, a most significant protein target within the PPI subnetwork.   
     
     
         2 . The method of  claim 1 , further comprising:
 displaying the most significant protein target to a user.   
     
     
         3 . The method of  claim 1 , further comprising:
 storing, in a data repository, the genomic information and the PPI data.   
     
     
         4 . The method of  claim 3 , wherein the at least one source is at least one selected from a group consisting of an academic database, a public database, and a private database. 
     
     
         5 . The method of  claim 3 , wherein the genomic information is at least one transcription data selected from a group consisting of messenger RNA (mRNA), RNA sequencing (RNA-seq), and Clustered regularly interspaced short palindromic repeats (CRISPR). 
     
     
         6 . The method of  claim 5 , wherein thermodynamic measure is Gibbs free energy for each of the protein nodes within the PPI data is computed using the transcription data and an equation of: 
       
         
           
             
               
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                     c 
                     i 
                   
                   
                     
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                         j 
                         = 
                         i 
                       
                     
                     
                       c 
                       j 
                     
                   
                 
               
             
           
         
       
       and an overall Gibbs free energy of all of the protein nodes within the PPI data is computed using an equation of: 
       
         
           
             
               qG 
               = 
               
                 
                   ∑ 
                   i 
                 
                 
                   G 
                   i 
                 
               
             
           
         
       
     
     
         7 . The method of  claim 1 , wherein the PPI subnetwork is a persistent homology that is extracted from the energy landscape of the PPI data using the topological filtration based on a user set threshold. 
     
     
         8 . The method of  claim 7 , wherein the user set threshold is between 5 to 7000. 
     
     
         9 . The method of  claim 1 , wherein the Betti number of the PPI subnetwork is computed based on the number of rings of four or more proteins nodes within the PPI subnetwork. 
     
     
         10 . The method of  claim 1 , wherein the Betti numbers and respective removed protein nodes are stored in an array. 
     
     
         11 . The method of  claim 1 , wherein the change in the Betti number represents an effect that the single protein node has on a network complexity of the PPI data and the single removed protein node that causes a highest drop of the network complexity is the most significant protein target. 
     
     
         12 . A computing system that selects a protein target for therapeutic application, comprising:
 a processing circuitry configured to execute instructions to:
 access genomic information and protein-protein interaction (PPI) data comprising a network of protein nodes from at least one source; 
 compute, using the genomic information and the PPI data, a thermodynamic measure for each of the protein nodes within the network; 
 generate an energy landscape data corresponding to the network and the thermodynamic measure; 
 generate a PPI subnetwork by applying a topological filtration to the energy landscape of the PPI data; 
 compute a first Betti number for the PPI subnetwork; 
 sequentially remove a first protein node from the PPI subnetwork; 
 compute a second Betti number for the PPI subnetwork with the first protein node removed; 
 compute a change between the first Betti number and the second Betti number; 
 replace the first protein node into the PPI subnetwork; 
 sequentially remove a second protein node different from the first protein node from the PPI subnetwork; 
 compute a third Betti number for the PPI subnetwork with the second protein node removed and first protein node replaced; 
 compute a change between the first Betti number and the third Betti number; and 
 determine, based on the change between the first Betti number and the second Betti number and the change between the first Betti number and the third Betti number, a most significant protein target within the PPI subnetwork; and 
   a display circuitry configured to execute instructions to display the most significant protein target to a user.   
     
     
         13 . The system of  claim 12 , further comprising:
 a data repository configured to store the genomic information and the PPI data.   
     
     
         14 . A non-transitory computer-readable medium having instructions stored thereon that, in response to execution by the computer system, cause the computer system to perform operations comprising:
 computing, using the genomic information and the PPI data, a thermodynamic measure for each of the protein nodes within the network;   generating an energy landscape data corresponding to the network and the thermodynamic measure;   generating a PPI subnetwork by applying a topological filtration to the energy landscape of the PPI data;   computing a first Betti number for the PPI subnetwork;   sequentially removing a first protein node from the PPI subnetwork;   computing a second Betti number for the PPI subnetwork with the first protein node removed;   computing a change between the first Betti number and the second Betti number;   replacing the first protein node into the PPI subnetwork;   sequentially removing a second protein node different from the first protein node from the PPI subnetwork;   computing a third Betti number for the PPI subnetwork with the second protein node removed and first protein node replaced;   computing a change between the first Betti number and the third Betti number; and   determining, based on the change between the first Betti number and the second Betti number and the change between the first Betti number and the third Betti number, a most significant protein target within the PPI subnetwork.   
     
     
         15 . The non-transitory computer-readable medium of  claim 14 , wherein instructions stored thereon that, in response to execution by the computer system, cause the computer system to perform operations further comprising displaying the most significant protein target to a user.