Structural analysis of α-fetoprotein (AFP)-like peptides with anti-breast-cancer properties.

The abundance of α-fetoprotein (AFP), a natural protein produced by the fetal yolk sac during pregnancy, correlates with lower incidence of estrogen receptor positive (ER+) breast cancer. The pharmacophore region of AFP has been narrowed down to a four amino acid (AA) region in the third domain of the 591 AA peptide. Our computational study focuses on a 4-mer segment consisting of the amino acids threonine-proline-valine-asparagine (TPVN). We have run replica exchange molecular dynamics (REMD) simulations and used 120 configurational snapshots from the total trajectory as starting configurations for quantum chemical calculations. We optimized structures using semiempirical (PM3, PM6, PM6-D2, PM6-H2, PM6-DH+, PM6-DH2) and density functional methods (TPSS, PBE0, M06-2X). By comparing the accuracy of these methods against RI-MP2 benchmarks, we devised a protocol for calculating the lowest energy conformers of these peptides accurately and efficiently. This protocol screens out high-energy conformers using lower levels of theory and outlines a general method for predicting small peptide structures.

[1]  Xue Li,et al.  Conformational analysis and parallel QM/MM X-ray refinement of protein bound anti-Alzheimer drug donepezil. , 2013, Journal of chemical theory and computation.

[2]  Brooks H. Pate,et al.  Broadband Fourier transform rotational spectroscopy for structure determination: The water heptamer , 2013 .

[3]  Dhruva K. Chakravorty,et al.  Energetics of zinc-mediated interactions in the allosteric pathways of metal sensor proteins. , 2013, Journal of the American Chemical Society.

[4]  J. Perdew,et al.  Performance of meta-GGA Functionals on General Main Group Thermochemistry, Kinetics, and Noncovalent Interactions. , 2013, Journal of chemical theory and computation.

[5]  A. Roitberg,et al.  Hydrophobic Effect Drives Oxygen Uptake in Myoglobin via Histidine E7* , 2013, The Journal of Biological Chemistry.

[6]  A. Roitberg,et al.  Enzyme dynamics and catalysis in the mechanism of DNA polymerase , 2012, Theoretical Chemistry Accounts.

[7]  Adrian E. Roitberg,et al.  pH-Dependent Conformational Changes in Proteins and Their Effect on Experimental pKas: The Case of Nitrophorin 4 , 2012, PLoS Comput. Biol..

[8]  G. Shields,et al.  Computational study of the hydration of sulfuric acid dimers: implications for acid dissociation and aerosol formation. , 2012, The journal of physical chemistry. A.

[9]  A. Roitberg,et al.  Enhancing Conformation and Protonation State Sampling of Hen Egg White Lysozyme Using pH Replica Exchange Molecular Dynamics. , 2012, Journal of chemical theory and computation.

[10]  Annia Galano,et al.  On the free radical scavenging mechanism of protocatechuic acid, regeneration of the catechol group in aqueous solution , 2012, Theoretical Chemistry Accounts.

[11]  Holger Gohlke,et al.  MMPBSA.py: An Efficient Program for End-State Free Energy Calculations. , 2012, Journal of chemical theory and computation.

[12]  A. Roitberg,et al.  pH-replica exchange molecular dynamics in proteins using a discrete protonation method. , 2012, The journal of physical chemistry. B.

[13]  Bill R. Miller,et al.  Wide-open flaps are key to urease activity. , 2012, Journal of the American Chemical Society.

[14]  Brooks H. Pate,et al.  Structures of Cage, Prism, and Book Isomers of Water Hexamer from Broadband Rotational Spectroscopy , 2012, Science.

[15]  G. Shields,et al.  Hydration of the bisulfate ion: atmospheric implications. , 2012, The journal of physical chemistry. A.

[16]  Kenneth M Merz,et al.  Conformational Analysis of Free and Bound Retinoic Acid. , 2012, Journal of chemical theory and computation.

[17]  Bing Wang,et al.  Simulations of allosteric motions in the zinc sensor CzrA. , 2012, Journal of the American Chemical Society.

[18]  G. Shields,et al.  Quantum mechanical study of sulfuric acid hydration: atmospheric implications. , 2012, The journal of physical chemistry. A.

[19]  A. Roitberg,et al.  Free energy study of the catalytic mechanism of Trypanosoma cruzi trans-sialidase. From the Michaelis complex to the covalent intermediate. , 2011, Biochemistry.

[20]  A. Tkatchenko,et al.  Dispersion Interactions with Density-Functional Theory: Benchmarking Semiempirical and Interatomic Pairwise Corrected Density Functionals. , 2011, Journal of chemical theory and computation.

[21]  S. Grimme,et al.  Performance of the van der Waals Density Functional VV10 and (hybrid)GGA Variants for Thermochemistry and Noncovalent Interactions. , 2011, Journal of chemical theory and computation.

[22]  Berhane Temelso,et al.  Benchmark structures and binding energies of small water clusters with anharmonicity corrections. , 2011, The journal of physical chemistry. A.

[23]  C. Simmerling,et al.  Energetic preference of 8-oxoG eversion pathways in a DNA glycosylase. , 2011, Journal of the American Chemical Society.

[24]  J. Yates.  A century of mass spectrometry: from atoms to proteomes , 2011, Nature Methods.

[25]  Janine Cossy,et al.  Peptides targeting estrogen receptor alpha-potential applications for breast cancer treatment. , 2011, Current pharmaceutical design.

[26]  G. Mizejewski.  Mechanism of Cancer Growth Suppression of Alpha-Fetoprotein Derived Growth Inhibitory Peptides (GIP): Comparison of GIP-34 versus GIP-8 (AFPep). Updates and Prospects , 2011, Cancers.

[27]  Stefan Grimme,et al.  Effect of the damping function in dispersion corrected density functional theory , 2011, J. Comput. Chem..

[28]  Kenneth M. Merz,et al.  The Energy Computation Paradox and ab initio Protein Folding , 2011, PloS one.

[29]  B. Sumpter,et al.  Density-functional approaches to noncovalent interactions: a comparison of dispersion corrections (DFT-D), exchange-hole dipole moment (XDM) theory, and specialized functionals. , 2011, The Journal of chemical physics.

[30]  Dardo N. Ferreiro,et al.  p38γ activation triggers dynamical changes in allosteric docking sites. , 2011, Biochemistry.

[31]  D. Truhlar,et al.  Density Functional Theory for Reaction Energies: Test of Meta and Hybrid Meta Functionals, Range-Separated Functionals, and Other High-Performance Functionals , 2011 .

[32]  T. Schlick,et al.  Biomolecular modeling and simulation: a field coming of age , 2011, Quarterly Reviews of Biophysics.

[33]  J. Brédas,et al.  An Error and Efficiency Analysis of Approximations to Møller−Plesset Perturbation Theory , 2010 .

[34]  G. Shields,et al.  Accurate predictions of water cluster formation, (H₂O)(n=2-10). , 2010, The journal of physical chemistry. A.

[35]  H. Orland,et al.  Dominant folding pathways of a peptide chain from ab initio quantum-mechanical simulations. , 2010, The Journal of chemical physics.

[36]  F. Neese,et al.  Efficient Structure Optimization with Second-Order Many-Body Perturbation Theory: The RIJCOSX-MP2 Method. , 2010, Journal of chemical theory and computation.

[37]  Pavel Hobza,et al.  Stabilization and structure calculations for noncovalent interactions in extended molecular systems based on wave function and density functional theories. , 2010, Chemical reviews.

[38]  S. Grimme,et al.  A consistent and accurate ab initio parametrization of density functional dispersion correction (DFT-D) for the 94 elements H-Pu. , 2010, The Journal of chemical physics.

[39]  G. Shields,et al.  Atmospheric implications for formation of clusters of ammonium and 1-10 water molecules. , 2010, The journal of physical chemistry. A.

[40]  C. Sherrill.  Frontiers in electronic structure theory. , 2010, The Journal of chemical physics.

[41]  Michael Levitt,et al.  Super-resolution biomolecular crystallography with low-resolution data , 2010, Nature.

[42]  M. Korth,et al.  A Transferable H-Bonding Correction for Semiempirical Quantum-Chemical Methods. , 2010, Journal of chemical theory and computation.

[43]  Kenneth M Merz,et al.  Divide-and-Conquer Hartree-Fock Calculations on Proteins. , 2010, Journal of chemical theory and computation.

[44]  Daniel J. Sindhikara,et al.  Apo and nickel-bound forms of the Pyrococcus horikoshii species of the metalloregulatory protein: NikR characterized by molecular dynamics simulations. , 2009, Biochemistry.

[45]  A. Roitberg,et al.  Computational studies of ammonia channel function in glutamine 5'-phosphoribosylpyrophosphate amidotransferase. , 2009, Biochemistry.

[46]  Ross C Walker,et al.  Are current semiempirical methods better than force fields? A study from the thermodynamics perspective. , 2009, The journal of physical chemistry. A.

[47]  F. Neese,et al.  Comparison of two efficient approximate Hartee–Fock approaches , 2009 .

[48]  Donald G Truhlar,et al.  Universal Solvation Model Based on the Generalized Born Approximation with Asymmetric Descreening. , 2009, Journal of chemical theory and computation.

[49]  James J. P. Stewart,et al.  Application of the PM6 method to modeling proteins , 2009, Journal of molecular modeling.

[50]  Jindřich Fanfrlík,et al.  Semiempirical Quantum Chemical PM6 Method Augmented by Dispersion and H-Bonding Correction Terms Reliably Describes Various Types of Noncovalent Complexes. , 2009, Journal of chemical theory and computation.

[51]  C. Simmerling,et al.  Recent Advances in the Study of the Bioactive Conformation of Taxol , 2009, ChemMedChem.

[52]  A. Roitberg,et al.  Modulation of catalytic function by differential plasticity of the active site: case study of Trypanosoma cruzi trans-sialidase and Trypanosoma rangeli sialidase. , 2009, Biochemistry.

[53]  Kenneth M. Merz,et al.  Importance of dispersion and electron correlation in ab initio protein folding. , 2009, The journal of physical chemistry. B.

[54]  C. Cramer,et al.  Universal solvation model based on solute electron density and on a continuum model of the solvent defined by the bulk dielectric constant and atomic surface tensions. , 2009, The journal of physical chemistry. B.

[55]  G. Shields.  Computational approaches for the design of peptides with anti-breast cancer properties. , 2009, Future medicinal chemistry.

[56]  G. Shields,et al.  Antiestrogenic and anticancer activities of peptides derived from the active site of alpha‐fetoprotein , 2009, Journal of peptide science : an official publication of the European Peptide Society.

[57]  F. Neese,et al.  Efficient, approximate and parallel Hartree–Fock and hybrid DFT calculations. A ‘chain-of-spheres’ algorithm for the Hartree–Fock exchange , 2009 .

[58]  M. Rosales-Hernández,et al.  Molecular modeling applied to anti-cancer drug development. , 2009, Anti-cancer agents in medicinal chemistry.

[59]  C. Simmerling,et al.  Drug pressure selected mutations in HIV-1 protease alter flap conformations. , 2009, Journal of the American Chemical Society.

[60]  C. Cramer,et al.  A universal approach to solvation modeling. , 2008, Accounts of chemical research.

[61]  Melinda Layten,et al.  Solution structure of HIV-1 protease flaps probed by comparison of molecular dynamics simulation ensembles and EPR experiments. , 2008, Journal of the American Chemical Society.

[62]  Pavel Hobza,et al.  Benchmark database on isolated small peptides containing an aromatic side chain: comparison between wave function and density functional theory methods and empirical force field. , 2008, Physical chemistry chemical physics : PCCP.

[63]  G. Shields,et al.  Hydration of OCS with one to four water molecules in atmospheric and laboratory conditions. , 2008, The journal of physical chemistry. A.

[64]  Asim Okur,et al.  Evaluation of Salt Bridge Structure and Energetics in Peptides Using Explicit, Implicit, and Hybrid Solvation Models. , 2008, Journal of chemical theory and computation.

[65]  D. Truhlar,et al.  The M06 suite of density functionals for main group thermochemistry, thermochemical kinetics, noncovalent interactions, excited states, and transition elements: two new functionals and systematic testing of four M06-class functionals and 12 other functionals , 2008 .

[66]  A. Roitberg,et al.  Bond or cage effect: how nitrophorins transport and release nitric oxide. , 2008, Journal of the American Chemical Society.

[67]  J. Stewart.  Optimization of parameters for semiempirical methods V: Modification of NDDO approximations and application to 70 elements , 2007, Journal of molecular modeling.

[68]  Katrina W. Lexa,et al.  Computational design and experimental discovery of an antiestrogenic peptide derived from alpha-fetoprotein. , 2007, Journal of the American Chemical Society.

[69]  G. Shields,et al.  In search of CS2(H2O)(n=1-4) clusters. , 2007, The Journal of chemical physics.

[70]  D. Raleigh,et al.  Reconciling the solution and X-ray structures of the villin headpiece helical subdomain: molecular dynamics simulations and double mutant cycles reveal a stabilizing cation-pi interaction. , 2007, Biochemistry.

[71]  Jirí Cerný,et al.  Density functional theory augmented with an empirical dispersion term. Interaction energies and geometries of 80 noncovalent complexes compared with ab initio quantum mechanics calculations , 2007, J. Comput. Chem..

[72]  Jacopo Tomasi,et al.  Dispersion and repulsion contributions to the solvation free energy: Comparison of quantum mechanical and classical approaches in the polarizable continuum model , 2006, J. Comput. Chem..

[73]  Stefan Grimme,et al.  Semiempirical GGA‐type density functional constructed with a long‐range dispersion correction , 2006, J. Comput. Chem..

[74]  V. Hornak,et al.  Comparison of multiple Amber force fields and development of improved protein backbone parameters , 2006, Proteins.

[75]  Dimas Suárez,et al.  Quantum mechanical and molecular dynamics simulations of ureases and Zn β‐lactamases , 2006, Journal of computational chemistry.

[76]  G. Mizejewski,et al.  Anticancer versus antigrowth activities of three analogs of the growth-inhibitory peptide: relevance to physicochemical properties. , 2006, Anticancer research.

[77]  Roberto Improta,et al.  A polarizable continuum approach for the study of heterogeneous dielectric environments. , 2006, The Journal of chemical physics.

[78]  G. Butterstein,et al.  Survey of functional activities of alpha-fetoprotein derived growth inhibitory peptides: review and prospects. , 2006, Current protein & peptide science.

[79]  Viktor Hornak,et al.  HIV-1 protease flaps spontaneously open and reclose in molecular dynamics simulations. , 2006, Proceedings of the National Academy of Sciences of the United States of America.

[80]  Holger Gohlke,et al.  The Amber biomolecular simulation programs , 2005, J. Comput. Chem..

[81]  Donald G Truhlar,et al.  SM6:  A Density Functional Theory Continuum Solvation Model for Calculating Aqueous Solvation Free Energies of Neutrals, Ions, and Solute-Water Clusters. , 2005, Journal of chemical theory and computation.

[82]  G. Shields,et al.  Global search for minimum energy (H2O)n clusters, n = 3-5. , 2005, The journal of physical chemistry. A.

[83]  J. Tomasi,et al.  Quantum mechanical continuum solvation models. , 2005, Chemical reviews.

[84]  A. Roitberg,et al.  Multiple-steering QM-MM calculation of the free energy profile in chorismate mutase. , 2005, Journal of the American Chemical Society.

[85]  J. Tomasi,et al.  A time-dependent polarizable continuum model: theory and application. , 2005, The Journal of chemical physics.

[86]  Thomas Meissner,et al.  The complex dielectric constant of pure and sea water from microwave satellite observations , 2004, IEEE Transactions on Geoscience and Remote Sensing.

[87]  K. Merz,et al.  Enzymatic catalysis of urea decomposition: elimination or hydrolysis? , 2004, Journal of the American Chemical Society.

[88]  Stefan Grimme,et al.  Accurate description of van der Waals complexes by density functional theory including empirical corrections , 2004, J. Comput. Chem..

[89]  C. Cramer,et al.  New Universal Solvation Model and Comparison of the Accuracy of the SM5.42R, SM5.43R, C-PCM, D-PCM, and IEF-PCM Continuum Solvation Models for Aqueous and Organic Solvation Free Energies and for Vapor Pressures , 2004 .

[90]  H. Jacobson,et al.  Synthetic peptide derived from alpha-fetoprotein inhibits growth of human breast cancer: investigation of the pharmacophore and synthesis optimization. , 2004, The journal of peptide research : official journal of the American Peptide Society.

[91]  G. Scuseria,et al.  Climbing the density functional ladder: nonempirical meta-generalized gradient approximation designed for molecules and solids. , 2003, Physical review letters.

[92]  Frederick R. Manby,et al.  Fast linear scaling second-order Møller-Plesset perturbation theory (MP2) using local and density fitting approximations , 2003 .

[93]  Darrin M. York,et al.  Fast approximate methods for calculating nucleic acid base pair interaction energies , 2003, J. Comput. Chem..

[94]  A. Roitberg,et al.  Smaller and faster: the 20-residue Trp-cage protein folds in 4 micros. , 2002, Journal of the American Chemical Society.

[95]  A. Roitberg,et al.  All-atom structure prediction and folding simulations of a stable protein. , 2002, Journal of the American Chemical Society.

[96]  Tomas Lozano-Perez,et al.  De novo determination of peptide structure with solid-state magic-angle spinning NMR spectroscopy , 2002, Proceedings of the National Academy of Sciences of the United States of America.

[97]  H. Jacobson,et al.  A peptide derived from α-fetoprotein prevents the growth of estrogen-dependent human breast cancers sensitive and resistant to tamoxifen , 2002, Proceedings of the National Academy of Sciences of the United States of America.

[98]  B. Berne,et al.  The free energy landscape for β hairpin folding in explicit water , 2001, Proceedings of the National Academy of Sciences of the United States of America.

[99]  G. Shields,et al.  Further Quantum Mechanical Evidence that Difluorotoluene Does Not Hydrogen Bond , 2001 .

[100]  S. L. Dixon,et al.  Linear scaling molecular orbital calculations of biological systems using the semiempirical divide and conquer method , 2000, J. Comput. Chem..

[101]  Dimas Suárez,et al.  Critical assessment of the performance of the semiempirical divide and conquer method for single point calculations and geometry optimizations of large chemical systems , 2000 .

[102]  Kenneth M. Merz,et al.  Quantum mechanical/quantum mechanical methods. I. A divide and conquer strategy for solving the Schrödinger equation for large molecular systems using a composite density functional–semiempirical Hamiltonian , 2000 .

[103]  H. Jacobson,et al.  Alpha-fetoprotein-derived antiestrotrophic octapeptide. , 2000, Biochimica et biophysica acta.

[104]  D. Case,et al.  Modification of the Generalized Born Model Suitable for Macromolecules , 2000 .

[105]  C. Cramer,et al.  Implicit Solvation Models: Equilibria, Structure, Spectra, and Dynamics. , 1999, Chemical reviews.

[106]  V. Barone,et al.  Toward reliable density functional methods without adjustable parameters: The PBE0 model , 1999 .

[107]  X. Daura,et al.  Peptide Folding: When Simulation Meets Experiment , 1999 .

[108]  J. A. Calvin,et al.  Levels of maternal serum alpha-fetoprotein (AFP) in pregnant women and subsequent breast cancer risk. , 1998, American journal of epidemiology.

[109]  X. Daura,et al.  Reversible peptide folding in solution by molecular dynamics simulation. , 1998, Journal of molecular biology.

[110]  M. Orozco,et al.  Molecular Dynamics Simulation of a PNA·DNA·PNA Triple Helix in Aqueous Solution , 1998 .

[111]  Jacopo Tomasi,et al.  Geometry optimization of molecular structures in solution by the polarizable continuum model , 1998, J. Comput. Chem..

[112]  G. Shields,et al.  Comparison of experimental and theoretical structures of a transition state analogue used for the induction of anti-cocaine catalytic antibodies , 1997 .

[113]  F. Weigend,et al.  RI-MP2: first derivatives and global consistency , 1997 .

[114]  Jacopo Tomasi,et al.  A new definition of cavities for the computation of solvation free energies by the polarizable continuum model , 1997 .

[115]  Jacopo Tomasi,et al.  A new integral equation formalism for the polarizable continuum model: Theoretical background and applications to isotropic and anisotropic dielectrics , 1997 .

[116]  M. Orozco,et al.  Molecular Dynamics Simulations of the d(T·A·T) Triple Helix , 1997 .

[117]  J. Tomasi,et al.  Ab initio study of solvated molecules: A new implementation of the polarizable continuum model , 1996 .

[118]  G. Mizejewski,et al.  Alpha-fetoprotein derived synthetic peptides: assay of an estrogen-modifying regulatory segment , 1996, Molecular and Cellular Endocrinology.

[119]  D. Bernholdt,et al.  Large-scale correlated electronic structure calculations: the RI-MP2 method on parallel computers , 1996 .

[120]  Andreas Klamt,et al.  Incorporation of solvent effects into density functional calculations of molecular energies and geometries , 1995 .

[121]  G. Shields,et al.  Quantum‐Mechanical investigation of large water clusters , 1994 .

[122]  G. Shields,et al.  Hydrogen bonding of nucleotide base pairs: Application of the PM3 method , 1994 .

[123]  Karl N. Kirschner,et al.  Modeling of magic water clusters (H2O)20 and (H2O)21H+ with the PM3 quantum‐mechanical method , 1993, J. Comput. Chem..

[124]  George C. Shields,et al.  Ability of the PM3 quantum‐mechanical method to model intermolecular hydrogen bonding between neutral molecules , 1993, J. Comput. Chem..

[125]  Donald G. Truhlar,et al.  AM1-SM2 and PM3-SM3 parameterized SCF solvation models for free energies in aqueous solution , 1992, J. Comput. Aided Mol. Des..

[126]  Kenneth M. Merz,et al.  Study of hydrogen bonding interactions relevant to biomolecular structure and function , 1992 .

[127]  T. Steitz,et al.  Crystal structure of a CAP-DNA complex: the DNA is bent by 90 degrees , 1991, Science.

[128]  T. Steitz,et al.  Crystallization of Escherichia coli catabolite gene activator protein with its DNA binding site. The use of modular DNA. , 1990, Journal of molecular biology.

[129]  G. Mizejewski,et al.  Inhibition of estrogen-dependent breast cancer growth by a reaction product of alpha-fetoprotein and estradiol. , 1990, Cancer research.

[130]  M. Mann,et al.  Electrospray ionization for mass spectrometry of large biomolecules. , 1989, Science.

[131]  J. Stewart.  Optimization of parameters for semiempirical methods I. Method , 1989 .

[132]  J. Stewart.  Optimization of parameters for semiempirical methods II. Applications , 1989 .

[133]  T. H. Dunning.  Gaussian basis sets for use in correlated molecular calculations. I. The atoms boron through neon and hydrogen , 1989 .

[134]  K. Wüthrich.  NMR of proteins and nucleic acids , 1988 .

[135]  J. Kendrew,et al.  A Three-Dimensional Model of the Myoglobin Molecule Obtained by X-Ray Analysis , 1958, Nature.

[136]  Frank Neese,et al.  The ORCA program system , 2012 .

[137]  C. Simmerling,et al.  Molecular dynamics applied in drug discovery: the case of HIV-1 protease. , 2012, Methods in molecular biology.

[138]  W. Sierralta,et al.  A peptide derived from alpha-fetoprotein inhibits the proliferation induced by estradiol in mammary tumor cells in culture. , 2008, Oncology reports.

[139]  Kenneth M Merz,et al.  Assessment of Semiempirical Quantum Mechanical Methods for the Evaluation of Protein Structures. , 2007, Journal of chemical theory and computation.

[140]  Katrina W. Lexa,et al.  The search for low energy conformational families of small peptides: Searching for active conformations of small peptides in the absence of a known receptor , 2007 .

[141]  V. Hornak,et al.  Investigation of Salt Bridge Stability in a Generalized Born Solvent Model. , 2006, Journal of chemical theory and computation.

[142]  C. Brooks,et al.  From folding theories to folding proteins: a review and assessment of simulation studies of protein folding and unfolding. , 2001, Annual review of physical chemistry.

[143]  R. Maccoll,et al.  Studies on a growth-inhibitory peptide derived from alpha-fetoprotein and some analogs. , 2001, The journal of peptide research : official journal of the American Peptide Society.

[144]  A. Klamt,et al.  COSMO : a new approach to dielectric screening in solvents with explicit expressions for the screening energy and its gradient , 1993 .