Our laboratory uses both computational and experimental methods to improve our understanding of how protein structures mediate protein function. Here, we develop and use the tools of bioinformatics and computational structural biology to integrate the information coming out of the genome projects with available tertiary structural information. One primary goal of our computational work is to develop a methodology for "rational protein design" that can be used in our laboratory to engineer new functionalities into proteins.

Covalent docking predicts substrates for haloalkanoate dehalogenase superfamily phosphatases. London N, Farelli JD, Brown SD, Liu C, Huang H, Korczynska M, Al-Obaidi NF, Babbitt PC, Almo SC, Allen KN, Shoichet BK. Biochemistry. 2015 Jan 20;54(2):528-37. doi: 10.1021/bi501140k. Epub 2015 Jan 5. New insights about enzyme evolution from large scale studies of sequence and structure relationships. Brown SD, Babbitt PC. J Biol Chem. 2014 Oct 31;289(44):30221-8. doi: 10.1074/jbc.R114.569350. Epub 2014 Sep 10. Predicting the functions and specificity of triterpenoid synthases: a mechanism-based multi-intermediate docking approach. Tian BX, Wallrapp FH, Holiday GL, Chow JY, Babbitt PC, Poulter CD, Jacobson MP. PLoS Comput Biol. 2014 Oct 9;10(10):e1003874. doi: 10.1371/journal.pcbi.1003874. Prediction and characterization of enzymatic activities guided by sequence similarity and genome neighborhood networks. Zhao S, Sakai A, Zhang X, Vetting MW, Kumar R, Hillerich B, San Francisco B, Solbiati J, Steves A, Brown S, Akiva E, Barber A, Seidel RD, Babbitt PC, Almo SC, Gerlt JA, Jacobson MP. eLife. 2014 Jun 30;3. doi: 10.7554/eLife.03275. Prediction of substrates for glutathione transferases by covalent docking. Dong GQ, Calhoun S, Fan H, Kalyanaraman C, Branch MC, Mashiyama ST, London N, Jacobson MP, Babbitt PC, Shoichet BK, Armstrong RN, Sali A. J Chem Inf Model. 2014 Jun 23;54(6):1687-99. doi: 10.1021/ci5001554. Epub 2014 May 16. Mechanistic and bioinformatic investigation of a conserved active site helix in α-isopropylmalate synthase from Mycobacterium tuberculosis, a member of the DRE-TIM metallolyase superfamily. Casey AK, Hicks MA, Johnson JL, Babbitt PC, Frantom PA. Biochemistry. 2014 May 13;53(18):2915-25. doi: 10.1021/bi500246z. Epub 2014 Apr 22. Large-scale determination of sequence, structure, and function relationships in cytosolic glutathione transferases across the biosphere. Mashiyama ST, Malabanan MM, Akiva E, Bhosle R, Branch MC, Hillerich B, Jagessar K, Kim J, Patskovsky Y, Seidel RD, Stead M, Toro R, Vetting MW, Almo SC, Armstrong RN, Babbitt PC. PLoS Biol. 2014 Apr 22;12(4):e1001843. doi: 10.1371/journal.pbio.1001843. eCollection 2014 Apr. The Structure-Function Linkage Database. Akiva E, Brown S, Almonacid DE, Barber AE 2nd, Custer AF, Hicks MA, Huang CC, Lauck F, Mashiyama ST, Meng EC, Mischel D, Morris JH, Ojha S, Schnoes AM, Stryke D, Yunes JM, Ferrin TE, Holliday GL, Babbitt PC. Nucleic Acids Res. 2014 Jan 1;42(1):D521-30. doi: 10.1093/nar/gkt1130. Epub 2013 Nov 23. Discovery of new enzymes and metabolic pathways by using structure and genome context. Zhao S, Kumar R, Sakai A, Vetting MW, Wood BM, Brown S, Bonanno JB, Hillerich BS, Seidel RD, Babbitt PC, Almo SC, Sweedler JV, Gerlt JA, Cronan JE, Jacobson MP. Nature. 2013 Oct 31;502(7473):698-702. doi: 10.1038/nature12576. Consequences of domain insertion on sequence-structure divergence in a superfold. Pandya C, Brown S, Pieper U, Sali A, Dunaway-Mariano D, Babbitt PC, Xia Y, Allen KN. Proc Natl Acad Sci U S A. 2013 Sep 3;110(36):E3381-7. Epub 2013 Aug 19. Structure-guided discovery of the metabolite carboxy-SAM that modulates tRNA function. Kim J, Xiao H, Bonanno JB, Kalyanaraman C, Brown S, Tang X, Al-Obaidi NF, Patskovsky Y, Babbitt PC, Jacobson MP, Lee YS, Almo SC. Nature. 2013 Jun 6;498(7452):123-6. Epub 2013 May 15. Biases in the experimental annotations of protein function and their effect on our understanding of protein function space. Schnoes AM, Ream DC, Thorman AW, Babbitt PC, Friedberg I. PLoS Comput Biol. 2013 May;9(5):e1003063. Epub 2013 May 30. Prediction of function for the polyprenyl transferase subgroup in the isoprenoid synthase superfamily. Wallrapp FH, Pan JJ, Ramamoorthy G, Almonacid DE, Hillerich BS, Seidel R, Patskovsky Y, Babbitt PC, Almo SC, Jacobson MP, Poulter CD. Proc Natl Acad Sci U S A. 2013 Mar 26;110(13):E1196-202. Epub 2013 Mar 14. A large-scale evaluation of computational protein function prediction. Radivojac P, Clark WT, Oron TR, Schnoes AM, Wittkop T, Sokolov A, Graim K, Funk C, Verspoor K, Ben-Hur A, Pandey G, Yunes JM, Talwalkar AS, Repo S, Souza ML, Piovesan D, Casadio R, Wang Z, Cheng J, Fang H, Gough J, Koskinen P, Törönen P, Nokso-Koivisto J, Holm L, Cozzetto D, Buchan DW, Bryson K, Jones DT, Limaye B, Inamdar H, Datta A, Manjari SK, Joshi R, Chitale M, Kihara D, Lisewski AM, Erdin S, Venner E, Lichtarge O, Rentzsch R, Yang H, Romero AE, Bhat P, Paccanaro A, Hamp T, Kaßner R, Seemayer S, Vicedo E, Schaefer C, Achten D, Auer F, Boehm A, Braun T, Hecht M, Heron M, Hönigschmid P, Hopf TA, Kaufmann S, Kiening M, Krompass D, Landerer C, Mahlich Y, Roos M, Björne J, Salakoski T, Wong A, Shatkay H, Gatzmann F, Sommer I, Wass MN, Sternberg MJ, Škunca N, Supek F, Bošnjak M, Panov P, Džeroski S, Šmuc T, Kourmpetis YA, van Dijk AD, ter Braak CJ, Zhou Y, Gong Q, Dong X, Tian W, Falda M, Fontana P, Lavezzo E, Di Camillo B, Toppo S, Lan L, Djuric N, Guo Y, Vucetic S, Bairoch A, Linial M, Babbitt PC, Brenner SE, Orengo C, Rost B, Mooney SD, Friedberg I. Nat Methods. 2013 Mar;10(3):221-7. Epub 2013 Jan 27. A global comparison of the human and T. brucei degradomes gives insights about possible parasite drug targets. Mashiyama ST, Koupparis K, Caffrey CR, McKerrow JH, Babbitt PC. PLoS Negl Trop Dis. 2012;6(12):e1942. Epub 2012 Dec 6. Pythoscape: a framework for generation of large protein similarity networks. Barber AE 2nd, Babbitt PC. Bioinformatics. 2012 Nov 1;28(21):2845-6. Epub 2012 Sep 8. Conservation of caspase substrates across metazoans suggests hierarchical importance of signaling pathways over specific targets and cleavage site motifs in apoptosis. Crawford ED, Seaman JE, Barber AE 2nd, David DC, Babbitt PC, Burlingame AL, Wells JA. Cell Death Differ. 2012 Dec;19(12):2040-8. Epub 2012 Aug 24. Homology models guide discovery of diverse enzyme specificities among dipeptide epimerases in the enolase superfamily. Lukk T, Sakai A, Kalyanaraman C, Brown SD, Imker HJ, Song L, Fedorov AA, Fedorov EV, Toro R, Hillerich B, Seidel R, Patskovsky Y, Vetting MW, Nair SK, Babbitt PC, Almo SC, Gerlt JA, Jacobson MP. Proc Natl Acad Sci U S A. 2012 Mar 13;109(11):4122-7. Epub 2012 Mar 5. Divergent evolution in enolase superfamily: strategies for assigning functions. Gerlt JA, Babbitt PC, Jacobson MP, Almo SC. J Biol Chem. 2012 Jan 2;287(1):29-34. Epub 2011 Nov 8. Inference of functional properties from large-scale analysis of enzyme superfamilies. Brown SD, Babbitt PC. J Biol Chem. 2012 Jan 2;287(1):35-42. Epub 2011 Nov 8.