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.
[1] J. A. McCammon, B. R. Gelin, and M. Karplus, "Dynamics of folded
proteins," Nature, vol. 267, pp. 585-590, 1977.
[2] M. Karplus and J. A. McCammon, "Molecular dynamics simulations of
biomolecules," Nat. Struct. Biol., vol. 9, pp. 646-652, 2002.
[3] A. Warshel, "Molecular dynamics simulations of biological reactions,"
Acc. Chem. Res., vol. 35, pp. 385-395, 2002.
[4] S. J. Weiner, P. A. Kollman, D. A. Case, U. C. Singh, C. Ghio, G.
Alagona, et al., "A new force-field for molecular mechanical simulation
of nucleic-acids and proteins," J. Am. Chem. Soc., vol. 106, pp. 765-
784, 1984.
[5] S. J. Weiner, P. A. Kollman, D. T. Nguyen, and D. A. Case, "An allatom
force field for simulations of protein and nucleic acids," J.
Comput. Chem., vol. 7, pp. 230-252, 1986.
[6] W. D. Cornell, P. Cieplak, C. I. Bayly, I. R. Gould, K. M. Merz, D. M.
Fergunson, et al., "A 2nd generation force-field for the simulation of
proteins, nucleic-acids, and organic-molecules," J. Am. Chem. Soc., vol.
117, pp. 5179-5197, 1995.
[7] B. R. Brooks, R. E. Bruccoleri, B. D. Olafson, D. J. States, S.
Swaminathan, and M. Karplus, "CHARMM - a programm for
macromolecular energy, minimization, and dynamics calculations," J.
Comput. Chem., vol. 4, pp. 187-217, 1983.
[8] A. D. MacKerell, D. Bashford, M. Bellott, R. L. Dunbrack, J. D.
Evanseck, M. J. Field et al., "All-atom empirical potential for molecular
modeling and dynamics studies of proteins," J. Phys. Chem. B, vol. 102,
pp. 3586-3616, 1998.
[9] A. D. MacKerell, N. Banavali, and N. Foloppe, "Development and
current status of the CHARMM force field for nucleic acids,"
Biopolymers, vol. 56, pp. 257-265, 2000.
[10] W. L. Jorgensen and J. Tirado-Rives, "The OPLS [optimized potentials
for liquid simulations] potential functions for proteins, energy
minimizations for crystals of cyclic peptides and crambin," J. Am. Chem. Soc., vol. 110, pp. 1657-1666, 1988.
[11] J. Pranata, S. G. Wierschke, and W. L. Jorgensen, "Opls Potential
Functions for Nucleotide Bases - Relative Association Constants of
Hydrogen-Bonded Base-Pairs in Chloroform," J. Am. Chem. Soc., vol. 113, pp. 2810-2819, 1991.
[12] W. L. Jorgensen, D. S. Maxwell, and J. Tirado-Rives, "Development
and testing of the OPLS all-atom force field on conformational
energetics and properties of organic liquids," J. Am. Chem. Soc., vol.
118, pp. 11225-11236, 1996.
[13] A. T. Marques, P. A. Fernandes, and M. J. Ramos, "Molecular dynamics
simulations of the amyloid-beta binding alcohol dehydrogenase
(ABAD) enzyme," Bioorgan. Med. Chem., vol. 16, pp. 9511-9518, 2008.
[14] N. F. Bras, N. M. F. S. Cerqueira, P. A. Fernandes, and M. J. Ramos,
"Carbohydrate-binding modules from family 11: Understanding the
binding mode of polysaccharides," Int. J. Quantum Chem., vol. 108, pp.
2030-2040, 2008.
[15] A. Viegas, N. F. Bras, N. M. F. S. Cerqueira, P. A. Fernandes, J. A. M.
Prates, C. M. G. A. Fontes, et al., "Molecular determinants of ligand specificity in family 11 carbohydrate binding modules - an NMR, X-ray
crystallography and computational chemistry approach," FEBS J., vol.
275, pp. 2524-2535, 2008.
[16] A. T. P. Carvalho, M. Swart, J. N. P. van Stralen, P. A. Fernandes, M. J.
Ramos, and F. M. Bickelhaupt, "Mechanism of thioredoxin-catalyzed
disulfide reduction. Activation of the buried thiol and role of the variable active-site residues," J. Phys. Chem. B, vol. 112, pp. 2511-2523, 2008.
[17] A. T. P. Carvalho, P. A. Fernandes, and M. J. Ramos, "Insights on
resistance to reverse transcriptase: The different patterns of interaction
of the nucleoside reverse transcriptase inhibitors in the
deoxyribonucleotide triphosphate binding site relative to the normal
substrate," J. Med. Chem., vol. 49, pp. 7675-7682, 2006.
[18] S. F. Sousa, P. A. Fernandes, and M. J. Ramos, "Enzyme Flexibility and
the Catalytic Mechanism of Farnesyltransferase: Targeting the
Relation," J. Phys. Chem. B, vol. 112, pp. 8681-8691, 2008.
[19] S. F. Sousa, P. A. Fernandes, and M. J. Ramos, "Molecular Dynamics
Simulations on the Critical States of the Farnesyltransferase Enzyme,"
Bioorg. Med. Chem., pp. (10.1016/j.bmc.2009.03.055), 2009.
[20] S. F. Sousa, P. A. Fernandes, and M. J. Ramos, "Molecular dynamics
analysis of farnesyltransferase: A closer look into the amino acid
behavior," Int. J. Quant. Chem., vol. 108, pp. 1939-1950, 2008.
[21] N. M. F. S. Cerqueira, N. F. Bras, P. A. Fernandes, and M. J. Ramos,
"MADAMM: A multistaged docking with an automated molecular
modeling protocol," Proteins, vol. 74, pp. 192-206, 2009.
[22] S. F. Sousa, P. A. Fernandes, and M. J. Ramos, "Unraveling the
mechanism of the farnesyltransferase Enzyme," J. Biol. Inorg. Chem.,
vol. 10, pp. 3-10, 2005.
[23] S. F. Sousa, P. A. Fernandes, and M. J. Ramos, "Farnesyltransferase
inhibitors: A detailed chemical view on an elusive biological problem,"
Curr. Med. Chem., vol. 15, pp. 1478-1492, 2008.
[24] S. F. Sousa, P. A. Fernandes, and M. J. Ramos, "The Search for the
Mechanism of the Reaction Catalyzed by Farnesyltransferase,"
Chemistry, 2009.
[25] S. F. Sousa, P. A. Fernandes, and M. J. Ramos, "Farnesyltransferase--
New Insights into the Zinc-Coordination Sphere Paradigm: Evidence for
a Carboxylate-Shift Mechanism," Biophys. J., vol. 88, pp. 483-494,2005.
[26] S. F. Sousa, P. A. Fernandes, and M. J. Ramos, "Farnesyltransferase:
Theoretical Studies on Peptide Substrate Entrance - Thiol or Thiolate
Coordination?," J. Mol. Struct. (Theochem), vol. 729, pp. 125-129,
2005.
[27] S. F. Sousa, P. A. Fernandes, and M. J. Ramos, "The carboxylate-shift
in zinc enzymes: a computational study," J. Am. Chem. Soc., vol. 129,
pp. 1378-1385, 2007.
[28] S. F. Sousa, P. A. Fernandes, and M. J. Ramos, "Theoretical Studies on
Farnesyltransferase: The Distances Paradox Explained," Proteins, vol.
66, pp. 205-218, 2007.
[29] M. J. Ramos and P. A. Fernandes, "Computational enzymatic catalysis,"
Acc. Chem. Res., vol. 41, pp. 689-698, 2008.
[30] S. B. Long, P. J. Casey, and L. S. Beese, "Reaction path of protein
farnesyltransferase at atomic resolution," Nature, vol. 419, pp. 645-650,
2002.
[31] H. W. Park, S. R. Boduluri, J. F. Moomaw, P. J. Casey, and L. S. Beese,
"Crystal Structure of Protein Farnesyltransferase at 2.25 Angstrom
Resolution," Science, vol. 275, pp. 1800-1804, 1997.
[32] D. A. Tobin, J. S. Pickett, H. L. Hartman, C. A. Fierke, and J. E.
Penner-Hahn, "Structural characterization of the zinc site in protein
farnesyltransferase," J. Am. Chem. Soc., vol. 125, pp. 9962-9969,2003.
[33] S. F. Sousa, P. A. Fernandes, and M. J. Ramos, "Theoretical Studies on
Farnesyltransferase: Evidence for Thioether Product Coordination to the
Active-Site Zinc Sphere," J. Comput. Chem., vol. 28, pp. 1160-1168,
2007.
[34] N. M. F. S. A. Cerqueira, S. Pereira, P. A. Fernandes, and M. J. Ramos,
"Overview of ribonucleotide reductase inhibitors: an appealing target in
anti-tumour therapy," Curr. Med. Chem., vol. 12, pp. 1283-1294, 2005.
[35] N. M. F. S. A. Cerqueira, P. A. Fernandes, L. A. Eriksson, and M. J.
Ramos, "New insights into a critical biological control step of the
mechanism of ribonucleotide reductase," J. Mol. Struct. (Theochem),
vol. 709, pp. 53-65, 2004.
[36] N. M. F. S. A. Cerqueira, P. A. Fernandes, L. A. Eriksson, and M. J.
Ramos, "Ribonucleotide activation by enzyme ribonucleotide reductase:
understanding the role of the enzyme," J. Comput. Chem., vol. 25, pp.
2031-2037, 2004.
[37] N. M. F. S. A. Cerqueira, P. A. Fernandes, L. A. Eriksson, and M. J.
Ramos, "Dehydration of ribonucleotides catalysed by ribonucleotide
reductase: the role of the enzyme," Biophys. J., vol. 90, pp. 2109-2119,
2006.
[38] P. A. Fernandes, L. A. Eriksson, and M. J. Ramos, "The reduction of
ribonucleotides catalyzed by the enzyme ribonucleotide reductase,"
Theor. Chem. Acc., vol. 108, pp. 352-364, 2002.
[39] S. Pereira, N. M. F. S. A. Cerqueira, P. A. Fernandes, and M. J. Ramos,
"Computational studies on class I ribonucleotide reductase:
Understanding the mechanism of action and inhibition of a cornerstone
enzyme for the treatment of cancer," Eur. Biophys. J., vol. 35, pp. 125-
135, 2006.
[40] P. A. Fernandes and M. J. Ramos, "Theoretical studies on the mode of
inhibition of ribonucleotide reductase by 2'-substituted substrate
analogues," Chem. Eur. J., vol. 9, pp. 5916-5925, 2003.
[41] N. M. F. S. Cerqueira, P. A. Fernandes, and M. J. Ramos, "Enzyme
ribonucleotide reductase: Unraveling an enigmatic paradigm of enzyme
inhibition by furanone derivatives," J. Phys. Chem. B, vol. 110, pp.
21272-21281, 2006.
[42] S. Pereira, P. A. Fernandes, and M. J. Ramos, "Theoretical study of
ribonucleotide reductase mechanism-based inhibition by 2'-azido-2'-
deoxyribonucleoside 5'-diphosphates," J. Comput. Chem., vol. 25, pp.
227-237, 2004.
[43] S. Pereira, P. A. Fernandes, and M. J. Ramos, "Mechanism for
ribonucleotide reductase inactivation by the anticancer drug
gemcitabine," J. Comput. Chem., vol. 25, pp. 1286-1294, 2004.
[44] S. Pereira, P. A. Fernandes, and M. J. Ramos, "Theoretical study on the
inhibition of ribonucleotide reductase by 2'-mercapto-2'-
deoxyribonucleoside-5," J. Am. Chem. Soc., vol. 127, pp. 5174-5179,
2005.
[45] P. A. Fernandes and M. J. Ramos, "Theoretical studies on the
mechanism of inhibition of Ribonucleotide Reductase by (E)-2'-
Fluoromethylene-2'-deoxycitidine-5'-diphosphate," J. Am. Chem. Soc.,
vol. 125, pp. 6311-6322, 2003.
[46] A. Ghosh, "Just how good is DFT?," J. Biol. Inorg. Chem., vol. 11, pp.
671-673, 2006.
[47] N. E. Schultz, Y. Zhao, and D. G. Truhlar, "Density functionals for
inorganometallic and organometallic chemistry," J. Phys. Chem. A, vol.
109, pp. 11127-11143, 2005.
[48] P. Hohenberg and W. Kohn, "Inhomogeneous Electron Gas," Phys. Rev.
B, vol. 136, pp. B864, 1964.
[49] Y. Zhao and D. G. Truhlar, "Density functionals with broad
applicability in chemistry," Acc. Chem. Res., vol. 41, pp. 157-167,
2008.
[50] S. F. Sousa, P. A. Fernandes, and M. J. Ramos, "General Performance of
Density Functionals," J. Phys. Chem A, vol. 111, pp. 10439-10452,
2007.
[51] S. F. Sousa, P. A. Fernandes, and M. J. Ramos, "Comparative
assessment of theoretical methods for the determination of geometrical
properties in biological zinc complexes," J. Phys. Chem. B, vol. 111, pp.
9146-9152, 2007.
[52] P. Jurecka, J. Cerny, P. Hobza, and D. R. Salahub, "Density functional
theory augmented with an empirical dispersion term. Interaction
energies and geometries of 80 noncovalent complexes compared with ab
initio quantum mechanics calculations," J. Comput. Chem., vol. 28, pp.
555-569, 2007.
[53] A. Karton, A. Tarnopolsky, J. F. Lamere, G. C. Schatz, and J. M. L.
Martin, "Highly Accurate First-Principles Benchmark Data Sets for the
Parametrization and Validation of Density Functional and Other
Approximate Methods. Derivation of a Robust, Generally Applicable,
Double-Hybrid Functional for Thermochemistry and Thermochemical
Kinetics," J. Phys. Chem. A, vol. 112, pp. 12868-12886, 2008.
[54] Y. Zhao and D. G. Truhlar, "Density functionals for noncovalent
interaction energies of biological importance," J. Chem. Theor.
Comput., vol. 3, pp. 289-300, 2007.
[55] T. van Mourik, "Assessment of Density Functionals for Intramolecular
Dispersion-Rich Interactions," J. Chem. Theor. Comput., vol. 4, pp.
1610-1619, 2008.
[56] R. Peverati and K. K. Baldridge, "Implementation and Performance of
DFT-D with Respect to Basis Set and Functional for Study of
Dispersion Interactions in Nanoscale Aromatic Hydrocarbons," J. Chem.
Theor. Comput., vol. 4, pp. 2030-2048, 2008.
[57] N. F. Bras, S. A. Moura-Tamames, P. A. Fernandes, and M. J. Ramos,
"Mechanistic Studies on the Formation of Glycosidase-Substrate and
Glycosidase-Inhibitor Covalent Intermediates," J. Comput. Chem., vol.
29, pp. 2565-2574, 2008.
[58] I. S. Moreira, P. A. Fernandes, and M. J. Ramos, "Hot spots-A review of
the protein-protein interface determinant amino-acid residues," Proteins,
vol. 68, pp. 803-812, 007.
[59] S. Jones and J. M. Thornton, "Principles of protein-protein interactions,"
Proc. Natl. Acad. Sci. USA, vol. 93, pp. 13-20, 1996.
[60] A. A. Bogan and K. S. Thorn, "Anatomy of hot spots in protein
interfaces," J. Mol. Biol., vol. 280, pp. 1-9, 1998.
[61] T. Clackson and J. A. Wells, "A Hot-Spot of Binding-Energy in A
Hormone-Receptor Interface," Science, vol. 267, pp. 383-386, 1995.
[62] W. L. Delano, "Unraveling hot spots in binding interfaces: progress and
challenges," Curr. Opin. Struct. Biol., vol. 12, pp. 14-20, 2002.
[63] I. S. Moreira, P. A. Fernandes, and M. J. Ramos, "Detailed microscopic
study of the full ZipA : FtsZ interface," Proteins, vol. 63, pp. 811-821,
2006.
[64] I. S. Moreira, P. A. Fernandes, and M. J. Ramos, "Unraveling the
importance of protein-protein interaction: Application of a
computational alanine-scanning mutagenesis to the study of the IgG1
streptococcal protein G (C2 fragment) complex," J. Phys. Chem. B, vol.
110, pp. 10962-10969, 2006.
[65] I. S. Moreira, P. A. Fernandes, and M. J. Ramos, "Hot spot
computational identification: Application to the complex formed
between the hen egg white lysozyme (HEL) and the antibody HyHEL-
10," Int. J. Quant. Chem., vol. 107, pp. 299-310, 2007.
[66] I. S. Moreira, P. A. Fernandes, and M. J. Ramos, "Hot spot occlusion
from bulk water: A comprehensive study of the complex between the
lysozyme HEL and the antibody FVD1.3," J. Phys. Chem. B, vol. 111,
pp. 2697-2706, 2007.
[67] I. S. Moreira, P. A. Fernandes, and M. J. Ramos, "Unravelling Hot
Spots: a comprehensive computational mutagenesis study," Theor.
Chem. Acc., vol. 117, pp. 99-113, 2007.
[68] I. S. Moreira, P. A. Fernandes, and M. J. Ramos, "Accuracy of the
numerical solution of the Poisson-Boltzmann equation," J. Mol. Struct.
(Theochem), vol. 729, pp. 11-18, 2005.
[69] I. S. Moreira, P. A. Fernandes, and M. J. Ramos, "Computational
alanine scanning mutagenesis - An improved methodological approach,"
J. Comput. Chem., vol. 28, pp. 644-654, 2007.
[70] T. Kortemme and D. Baker, "A simple physical model for binding
energy hot spots in protein-protein complexes," Proc. Natl. Acad. Sci.
USA, vol. 99, pp. 14116-14121, 2002.
[71] E. Guney, N. Tuncbag, O. Keskin, and A. Gursoy, "HotSprint: database
of computational hot spots in protein interfaces," Nucleic Acids Res.,
vol. 36, pp. D662-D666, 2008.
[72] S. J. Darnell, D. Page, and J. C. Mitchell, "An automated decision-tree
approach to predicting protein interaction hot spots," Proteins, vol. 68,
pp. 813-823, 2007.
[73] D. A. Case, T. A. Darden, T. E. Cheatham III, C. L. Simmerling, J.
Wang, R. E. Duke, et al., "AMBER 8," University of California, San
Francisco, 2004.
[74] M. R. Shirts, J. W. Pitera, W. C. Swope, and V. S. Pande, "Extremely
precise free energy calculations of amino acid side chain analogs:
Comparison of common molecular mechanics force fields for proteins,"
J. Chem. Phys., vol. 119, pp. 5740-5761, 2003.
[75] J. W. Pitera and W. F. van Gunsteren, "A comparison of non-bonded
scaling approaches for free energy calculations," Mol. Simul., vol. 28,
pp. 45-65, 2002.
[76] A. Blondel, "Ensemble variance in free energy calculations by
thermodynamic integration: Theory, optimal "Alchemical" path, and
practical solutions," J. Comput. Chem., vol. 25, pp. 985-993, 2004.
[77] P. A. Kollman, I. Massova, C. Reyes, B. Kuhn, S. H. Huo, L. Chong, M.
Lee, T. Lee, Y. Duan, W. Wang, O. Donini, P. Cieplak, J. Srinivasan, D.
A. Case, and T. E. Cheatham, "Calculating structures and free energies
of complex molecules: Combining molecular mechanics and continuum
models," Acc. Chem. Res., vol. 33, pp. 889-897, 2000.
[78] M. A. S. Perez, P. A. Fernandes, and M. J. Ramos, "Drug design: New
inhibitors for HIV-1 protease based on Nelfinavir as lead," J. Mol.
Graph. Model., vol. 26, pp. 634-642, 2007.
[79] W. Wang and P. A. Kollman, "Computational study of protein
specificity: The molecular basis of HIV-1 protease drug resistance,"
Proc. Natl. Acad. Sci. USA, vol. 98, pp. 14937-14942, 2001.
[80] S. Gupta, L. M. Rodrigues, A. P. Esteves, A. M. F. Oliveira-Campos, M.
S. J. Nascimento, N. Nazareth, H. Cidade, M. P. Neves, F. Fernandes,
M. Pinto, N. M. F. S. A. Cerqueira, and N. Bras, "Synthesis of N-aryl-5-
amino-4-cyanopyrazole derivatives as potent xanthine oxidase
inhibitors," Eur. J. Med. Chem., vol. 43, pp. 771-780, 2007.
[81] M. L. Lamb and W. L. Jorgensen, "Computational approaches to
molecular recognition," Curr. Opin. Chem. Biol., vol. 1, pp. 449-457,
1997.
[82] C. N. Cavasotto and N. Singh, "Docking and high throughput docking:
Successes and the challenge of protein flexibility," Curr. Comput. Aided
Drug Des., vol. 4, pp. 221-234, 2008.
[83] S. F. Sousa, P. A. Fernandes, and M. J. Ramos, "Protein-ligand docking:
Current status and future challenges," Proteins, vol. 65, pp. 15-26, 2006.
[84] N. Brooijmans and I. D. Kuntz, "Molecular recognition and docking
algorithms," Ann. Rev. Biophys. Biomol. Struct., vol. 32, pp. 335-373,
2003.
[1] J. A. McCammon, B. R. Gelin, and M. Karplus, "Dynamics of folded
proteins," Nature, vol. 267, pp. 585-590, 1977.
[2] M. Karplus and J. A. McCammon, "Molecular dynamics simulations of
biomolecules," Nat. Struct. Biol., vol. 9, pp. 646-652, 2002.
[3] A. Warshel, "Molecular dynamics simulations of biological reactions,"
Acc. Chem. Res., vol. 35, pp. 385-395, 2002.
[4] S. J. Weiner, P. A. Kollman, D. A. Case, U. C. Singh, C. Ghio, G.
Alagona, et al., "A new force-field for molecular mechanical simulation
of nucleic-acids and proteins," J. Am. Chem. Soc., vol. 106, pp. 765-
784, 1984.
[5] S. J. Weiner, P. A. Kollman, D. T. Nguyen, and D. A. Case, "An allatom
force field for simulations of protein and nucleic acids," J.
Comput. Chem., vol. 7, pp. 230-252, 1986.
[6] W. D. Cornell, P. Cieplak, C. I. Bayly, I. R. Gould, K. M. Merz, D. M.
Fergunson, et al., "A 2nd generation force-field for the simulation of
proteins, nucleic-acids, and organic-molecules," J. Am. Chem. Soc., vol.
117, pp. 5179-5197, 1995.
[7] B. R. Brooks, R. E. Bruccoleri, B. D. Olafson, D. J. States, S.
Swaminathan, and M. Karplus, "CHARMM - a programm for
macromolecular energy, minimization, and dynamics calculations," J.
Comput. Chem., vol. 4, pp. 187-217, 1983.
[8] A. D. MacKerell, D. Bashford, M. Bellott, R. L. Dunbrack, J. D.
Evanseck, M. J. Field et al., "All-atom empirical potential for molecular
modeling and dynamics studies of proteins," J. Phys. Chem. B, vol. 102,
pp. 3586-3616, 1998.
[9] A. D. MacKerell, N. Banavali, and N. Foloppe, "Development and
current status of the CHARMM force field for nucleic acids,"
Biopolymers, vol. 56, pp. 257-265, 2000.
[10] W. L. Jorgensen and J. Tirado-Rives, "The OPLS [optimized potentials
for liquid simulations] potential functions for proteins, energy
minimizations for crystals of cyclic peptides and crambin," J. Am. Chem. Soc., vol. 110, pp. 1657-1666, 1988.
[11] J. Pranata, S. G. Wierschke, and W. L. Jorgensen, "Opls Potential
Functions for Nucleotide Bases - Relative Association Constants of
Hydrogen-Bonded Base-Pairs in Chloroform," J. Am. Chem. Soc., vol. 113, pp. 2810-2819, 1991.
[12] W. L. Jorgensen, D. S. Maxwell, and J. Tirado-Rives, "Development
and testing of the OPLS all-atom force field on conformational
energetics and properties of organic liquids," J. Am. Chem. Soc., vol.
118, pp. 11225-11236, 1996.
[13] A. T. Marques, P. A. Fernandes, and M. J. Ramos, "Molecular dynamics
simulations of the amyloid-beta binding alcohol dehydrogenase
(ABAD) enzyme," Bioorgan. Med. Chem., vol. 16, pp. 9511-9518, 2008.
[14] N. F. Bras, N. M. F. S. Cerqueira, P. A. Fernandes, and M. J. Ramos,
"Carbohydrate-binding modules from family 11: Understanding the
binding mode of polysaccharides," Int. J. Quantum Chem., vol. 108, pp.
2030-2040, 2008.
[15] A. Viegas, N. F. Bras, N. M. F. S. Cerqueira, P. A. Fernandes, J. A. M.
Prates, C. M. G. A. Fontes, et al., "Molecular determinants of ligand specificity in family 11 carbohydrate binding modules - an NMR, X-ray
crystallography and computational chemistry approach," FEBS J., vol.
275, pp. 2524-2535, 2008.
[16] A. T. P. Carvalho, M. Swart, J. N. P. van Stralen, P. A. Fernandes, M. J.
Ramos, and F. M. Bickelhaupt, "Mechanism of thioredoxin-catalyzed
disulfide reduction. Activation of the buried thiol and role of the variable active-site residues," J. Phys. Chem. B, vol. 112, pp. 2511-2523, 2008.
[17] A. T. P. Carvalho, P. A. Fernandes, and M. J. Ramos, "Insights on
resistance to reverse transcriptase: The different patterns of interaction
of the nucleoside reverse transcriptase inhibitors in the
deoxyribonucleotide triphosphate binding site relative to the normal
substrate," J. Med. Chem., vol. 49, pp. 7675-7682, 2006.
[18] S. F. Sousa, P. A. Fernandes, and M. J. Ramos, "Enzyme Flexibility and
the Catalytic Mechanism of Farnesyltransferase: Targeting the
Relation," J. Phys. Chem. B, vol. 112, pp. 8681-8691, 2008.
[19] S. F. Sousa, P. A. Fernandes, and M. J. Ramos, "Molecular Dynamics
Simulations on the Critical States of the Farnesyltransferase Enzyme,"
Bioorg. Med. Chem., pp. (10.1016/j.bmc.2009.03.055), 2009.
[20] S. F. Sousa, P. A. Fernandes, and M. J. Ramos, "Molecular dynamics
analysis of farnesyltransferase: A closer look into the amino acid
behavior," Int. J. Quant. Chem., vol. 108, pp. 1939-1950, 2008.
[21] N. M. F. S. Cerqueira, N. F. Bras, P. A. Fernandes, and M. J. Ramos,
"MADAMM: A multistaged docking with an automated molecular
modeling protocol," Proteins, vol. 74, pp. 192-206, 2009.
[22] S. F. Sousa, P. A. Fernandes, and M. J. Ramos, "Unraveling the
mechanism of the farnesyltransferase Enzyme," J. Biol. Inorg. Chem.,
vol. 10, pp. 3-10, 2005.
[23] S. F. Sousa, P. A. Fernandes, and M. J. Ramos, "Farnesyltransferase
inhibitors: A detailed chemical view on an elusive biological problem,"
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anti-tumour therapy," Curr. Med. Chem., vol. 12, pp. 1283-1294, 2005.
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2006.
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ribonucleotides catalyzed by the enzyme ribonucleotide reductase,"
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"Computational studies on class I ribonucleotide reductase:
Understanding the mechanism of action and inhibition of a cornerstone
enzyme for the treatment of cancer," Eur. Biophys. J., vol. 35, pp. 125-
135, 2006.
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inhibition of ribonucleotide reductase by 2'-substituted substrate
analogues," Chem. Eur. J., vol. 9, pp. 5916-5925, 2003.
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ribonucleotide reductase: Unraveling an enigmatic paradigm of enzyme
inhibition by furanone derivatives," J. Phys. Chem. B, vol. 110, pp.
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ribonucleotide reductase mechanism-based inhibition by 2'-azido-2'-
deoxyribonucleoside 5'-diphosphates," J. Comput. Chem., vol. 25, pp.
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gemcitabine," J. Comput. Chem., vol. 25, pp. 1286-1294, 2004.
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inhibition of ribonucleotide reductase by 2'-mercapto-2'-
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study of the full ZipA : FtsZ interface," Proteins, vol. 63, pp. 811-821,
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importance of protein-protein interaction: Application of a
computational alanine-scanning mutagenesis to the study of the IgG1
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between the hen egg white lysozyme (HEL) and the antibody HyHEL-
10," Int. J. Quant. Chem., vol. 107, pp. 299-310, 2007.
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from bulk water: A comprehensive study of the complex between the
lysozyme HEL and the antibody FVD1.3," J. Phys. Chem. B, vol. 111,
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of complex molecules: Combining molecular mechanics and continuum
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@article{"International Journal of Biological, Life and Agricultural Sciences:64469", author = "Sérgio F. Sousa and Nuno M. F. S. A. Cerqueira and Marta A. S. Perez and Irina S. Moreira and António J. M.Ribeiro and Ana R. A. P. Neves and Maria J. Ramos and Pedro A. Fernandes", title = "Recent Advances on Computational Proteomics", abstract = "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.
", keywords = "Enzyme, Molecular Dynamics, Protein, Quantum Mechanics.", volume = "3", number = "8", pages = "404-11", }
