In this work we report the recent progresses that have been achieved by our group in the last half decade on the field of computational proteomics. Specifically, we discuss the application of Molecular Dynamics Simulations and Electronic Structure Calculations in drug design, in the clarification of the structural and dynamic properties of proteins and enzymes and in the understanding of the catalytic and inhibition mechanism of cancer-related enzymes. A set of examples illustrate the concepts and help to introduce the reader into this important and fast moving field., {"references":["J. A. McCammon, B. R. Gelin, and M. Karplus, \"Dynamics of folded\nproteins,\" Nature, vol. 267, pp. 585-590, 1977.","M. Karplus and J. A. McCammon, \"Molecular dynamics simulations of\nbiomolecules,\" Nat. Struct. Biol., vol. 9, pp. 646-652, 2002.","A. Warshel, \"Molecular dynamics simulations of biological reactions,\"\nAcc. Chem. Res., vol. 35, pp. 385-395, 2002.","S. J. Weiner, P. A. Kollman, D. A. 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P. van Stralen, P. A. Fernandes, M. J.\nRamos, and F. M. Bickelhaupt, \"Mechanism of thioredoxin-catalyzed\ndisulfide reduction. Activation of the buried thiol and role of the variable active-site residues,\" J. Phys. Chem. B, vol. 112, pp. 2511-2523, 2008.\n[17] A. T. P. Carvalho, P. A. Fernandes, and M. J. Ramos, \"Insights on\nresistance to reverse transcriptase: The different patterns of interaction\nof the nucleoside reverse transcriptase inhibitors in the\ndeoxyribonucleotide triphosphate binding site relative to the normal\nsubstrate,\" J. Med. Chem., vol. 49, pp. 7675-7682, 2006.\n[18] S. F. Sousa, P. A. Fernandes, and M. J. Ramos, \"Enzyme Flexibility and\nthe Catalytic Mechanism of Farnesyltransferase: Targeting the\nRelation,\" J. Phys. Chem. B, vol. 112, pp. 8681-8691, 2008.\n[19] S. F. Sousa, P. A. Fernandes, and M. J. Ramos, \"Molecular Dynamics\nSimulations on the Critical States of the Farnesyltransferase Enzyme,\"\nBioorg. Med. Chem., pp. (10.1016/j.bmc.2009.03.055), 2009.\n[20] S. F. Sousa, P. A. Fernandes, and M. J. Ramos, \"Molecular dynamics\nanalysis of farnesyltransferase: A closer look into the amino acid\nbehavior,\" Int. J. Quant. Chem., vol. 108, pp. 1939-1950, 2008.\n[21] N. M. F. S. Cerqueira, N. F. Bras, P. A. Fernandes, and M. J. Ramos,\n\"MADAMM: A multistaged docking with an automated molecular\nmodeling protocol,\" Proteins, vol. 74, pp. 192-206, 2009.\n[22] S. F. Sousa, P. A. Fernandes, and M. J. Ramos, \"Unraveling the\nmechanism of the farnesyltransferase Enzyme,\" J. Biol. Inorg. Chem.,\nvol. 10, pp. 3-10, 2005.\n[23] S. F. Sousa, P. A. Fernandes, and M. J. Ramos, \"Farnesyltransferase\ninhibitors: A detailed chemical view on an elusive biological problem,\"\nCurr. Med. Chem., vol. 15, pp. 1478-1492, 2008.\n[24] S. F. Sousa, P. A. Fernandes, and M. J. Ramos, \"The Search for the\nMechanism of the Reaction Catalyzed by Farnesyltransferase,\"\nChemistry, 2009.\n[25] S. F. Sousa, P. A. Fernandes, and M. J. Ramos, \"Farnesyltransferase--\nNew Insights into the Zinc-Coordination Sphere Paradigm: Evidence for\na Carboxylate-Shift Mechanism,\" Biophys. J., vol. 88, pp. 483-494,2005.\n[26] S. F. Sousa, P. A. Fernandes, and M. J. Ramos, \"Farnesyltransferase: \nTheoretical Studies on Peptide Substrate Entrance - Thiol or Thiolate \nCoordination?,\" J. Mol. Struct. (Theochem), vol. 729, pp. 125-129, \n2005. \n[27] S. F. Sousa, P. A. Fernandes, and M. J. Ramos, \"The carboxylate-shift \nin zinc enzymes: a computational study,\" J. Am. Chem. Soc., vol. 129, \npp. 1378-1385, 2007. \n[28] S. F. Sousa, P. A. Fernandes, and M. J. Ramos, \"Theoretical Studies on \nFarnesyltransferase: The Distances Paradox Explained,\" Proteins, vol. \n66, pp. 205-218, 2007. \n[29] M. J. Ramos and P. A. Fernandes, \"Computational enzymatic catalysis,\" \nAcc. Chem. Res., vol. 41, pp. 689-698, 2008. \n[30] S. B. Long, P. J. Casey, and L. S. Beese, \"Reaction path of protein \nfarnesyltransferase at atomic resolution,\" Nature, vol. 419, pp. 645-650, \n2002. \n[31] H. W. Park, S. R. Boduluri, J. F. Moomaw, P. J. Casey, and L. S. Beese, \n\"Crystal Structure of Protein Farnesyltransferase at 2.25 Angstrom \nResolution,\" Science, vol. 275, pp. 1800-1804, 1997. \n[32] D. A. Tobin, J. S. Pickett, H. L. Hartman, C. A. Fierke, and J. E. \nPenner-Hahn, \"Structural characterization of the zinc site in protein \nfarnesyltransferase,\" J. Am. Chem. Soc., vol. 125, pp. 9962-9969,2003. \n[33] S. F. Sousa, P. A. Fernandes, and M. J. Ramos, \"Theoretical Studies on \nFarnesyltransferase: Evidence for Thioether Product Coordination to the \nActive-Site Zinc Sphere,\" J. Comput. Chem., vol. 28, pp. 1160-1168, \n2007. \n[34] N. M. F. S. A. Cerqueira, S. Pereira, P. A. Fernandes, and M. J. Ramos, \n\"Overview of ribonucleotide reductase inhibitors: an appealing target in \nanti-tumour therapy,\" Curr. Med. Chem., vol. 12, pp. 1283-1294, 2005. \n[35] N. M. F. S. A. Cerqueira, P. A. Fernandes, L. A. Eriksson, and M. J. \nRamos, \"New insights into a critical biological control step of the \nmechanism of ribonucleotide reductase,\" J. Mol. Struct. (Theochem), \nvol. 709, pp. 53-65, 2004. \n[36] N. M. F. S. A. Cerqueira, P. A. Fernandes, L. A. Eriksson, and M. J. \nRamos, \"Ribonucleotide activation by enzyme ribonucleotide reductase: \nunderstanding the role of the enzyme,\" J. Comput. Chem., vol. 25, pp. \n2031-2037, 2004. \n[37] N. M. F. S. A. Cerqueira, P. A. Fernandes, L. A. Eriksson, and M. J. \nRamos, \"Dehydration of ribonucleotides catalysed by ribonucleotide \nreductase: the role of the enzyme,\" Biophys. J., vol. 90, pp. 2109-2119, \n2006. \n[38] P. A. Fernandes, L. A. Eriksson, and M. J. Ramos, \"The reduction of \nribonucleotides catalyzed by the enzyme ribonucleotide reductase,\" \nTheor. Chem. Acc., vol. 108, pp. 352-364, 2002. \n[39] S. Pereira, N. M. F. S. A. Cerqueira, P. A. Fernandes, and M. J. Ramos, \n\"Computational studies on class I ribonucleotide reductase: \nUnderstanding the mechanism of action and inhibition of a cornerstone \nenzyme for the treatment of cancer,\" Eur. Biophys. J., vol. 35, pp. 125-\n135, 2006. \n[40] P. A. Fernandes and M. J. Ramos, \"Theoretical studies on the mode of \ninhibition of ribonucleotide reductase by 2'-substituted substrate \nanalogues,\" Chem. Eur. J., vol. 9, pp. 5916-5925, 2003. \n[41] N. M. F. S. Cerqueira, P. A. Fernandes, and M. J. Ramos, \"Enzyme \nribonucleotide reductase: Unraveling an enigmatic paradigm of enzyme \ninhibition by furanone derivatives,\" J. Phys. Chem. B, vol. 110, pp. \n21272-21281, 2006. \n[42] S. Pereira, P. A. Fernandes, and M. J. Ramos, \"Theoretical study of \nribonucleotide reductase mechanism-based inhibition by 2'-azido-2'-\ndeoxyribonucleoside 5'-diphosphates,\" J. Comput. Chem., vol. 25, pp. \n227-237, 2004. \n[43] S. Pereira, P. A. Fernandes, and M. J. 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