Study of enzymatic mechanisms

The increasing computing capacity of today;s computers together with our deeper understanding of enzyme structures allows us to conduct calculations on enzymatic mechanisms at the quantum chemical level. Such studies allow us to understand mechanims not investigatable by experimental techniques directly. The first system we modeled is chymotryopsin, an enzyme whose inhibitors are already studied in our lab by NMR spectroscopy.

Publications
Péter Hudáky and András Perczel:
A self-stabilized model of the chymotrypsin catalytic pocket. The energy profile of the overall catalytic cycle
Proteins (2006) 62:749-759.
[abstract]


Conformational studies of α-amino acids and peptides

Proteins and peptides are dynamic compounds with a remarkable degree of flexibility. Therefore, the exploration of the accessible conformations of peptide building blocks is of great importance. Muldidimensional conformational analysis (MDCA) is a powerfool tool that can be used for all available levels of molecular calculations, including quantum chemistry, used in our group. We have explored the conformational preferences of several aromatic (Phe, His) and aliphatic amino acid residues (Val, Pro, Ser, Cys, Asp, Ala, Gly) amino acid incorporating model peptides as well as as studied the accessible geometries of polar residues (Ser, Asp, O-GlcSer, selenoCys). Moreover, we are investigating the energetics of seconadry structure elements, namely α- and 3₁₀-helices, β-turns, and β-sheets at differennt levels of theory.

Selected publications
András Perczel, Zoltán Gáspári and Imre G. Csizmadia:
Structure and stability of β-sheets.
J. Comput. Chem. (2005) 26:1155-1168.
[abstract]


András Láng, Imre G. Csizmadia and András Perczel:
Peptide models XLV. Conformational properties of N-formyl-L-methioninamide and its relevance to methionine in proteins
Proteins (2005) 58(3):571-588.
[abstract]

Ilona Hudáky, Péter Hudáky and András Perczel:
Solvation model induced structural changes in peptides. A quantum chemical study on Ramachandran surfaces and conformers of alanine diamide using the polarizable continuum model
J. Comput. Chem. (2004) 25(12):1522-1531.
[abstract]

András Perczel, Péter Hudáky, Anna K. Füzéry and Imre G. Csizmadia:
Stability issues of covalently and noncovalently bonded peptide subunits
J. Comput. Chem. (2004) 25(8):1084-1100.
[abstract]

Ilona Hudáky, Róbert Kiss and András Perczel:
A nomenclature of peptide conformers.
J. Mol. Struct. (THEOCHEM) (2004) 675(1-3): 177-183.
[abstract]

Péter Hudáky and András Perczel:
Peptide models XLII. Ab initio study on conformational changes of N-formyl--histidinamide caused by protonation or deprotonation of its side chain.
J. Mol. Struct. (THEOCHEM) (2004) 675(1-3): 117-127.
[abstract]

Zoltán Gáspári, Ilona Hudáky, András Czajlik and András Perczel:
Is there an excuse for the non-conformist? Notes on the calculated energies, atom-atom contacts and natural abundance of the different conformers of alanine in proteins.
J. Mol. Struct. (THEOCHEM) (2004) 675(1-3): 141-148.
[abstract]

Ilona Hudáky, Zoltán Gáspári, Oliviero Carugo, Masa Cemazar, Sándor Pongor and András Perczel:
Vicinal disulfide bridge conformers by experimental methods and by ab initio and DFT molecular computations
Proteins (2004) 55(1): 152-168.
[abstract]

András Perczel, Imre Jákli and Imre G. Csizmadia:
Intrinsically stable secondary structure elements of proteins: a comprehensive study of folding units of proteins by computation and by analysis of data determined by X-ray crystallography
Chem. Eur. J. (2003) 9(21): 5332-5342
[abstract]

Péter Hudáky, Tamás Beke and András Perczel: Side-chain conformational potential energy surfaces associated with all major backbone folds of neutral tautomers of N- and C-protected L-histidine J. Mol. Struct. (THEOCHEM) (2002) 583(1-3): 117-135
[abstract]

Péter Hudáky, Ilona Hudáky and András Perczel: Protonated and deprotonated N-Formyl-L-histidinamide:an ab-initio study on side-chain potential energy surfaces of all major backbone conformers J. Mol. Struct. (THEOCHEM) (2002) 583(1-3): 199-213
[abstract]

Péter Hudáky, Imre Jákli, Attila G. Császár, András Perczel:
Peptide models XXXI. Conformational properties of hydrophobic residues shaping the core of proteins. An ab initio study of N-formyl-l-valinamide and N-formyl-L-phenyalaninamide.
J. Comput. Chem. (2001) 22: 732-751.
[abstract]

Igor A. Topol, Stanley K. Burt, Eugen Deretey, Ting-Hua Tang, András Perczel, Alexander Rashin, and Imre G. Csizmadia
α- and 3₁₀ -helix interconversion: A quantum-chemical study on polyalanine systems in the gas phase and in aqueous solvent.
J. Am. Chem. Soc. (2001) 123: 6054-6060.
[abstract]

András Perczel, Ödön Farkas, Imre G. Csizmadia:
Peptide models. 18. Hydroxymethyl side-chain induced backbone conformational shifts of For-l-Ser-NH2. All ab initio conformers of For-l-Ser-NH2.
J. Am. Chem. Soc. (1996) 118: 7809-7817.

András Perczel, Imre G. Csizmadia:
Searching for the simplest structural units to describe the 3-dimensional structure of proteins (Review).
Int..Rev. Phys. Chem. (1995) 14: 127-168.

András Perczel, Michael A. McAllister, Pál Császár, Imre G. Csizmadia:
Peptide models. 6. New beta-turn conformations from ab initio calculations confirmed by X-ray data of proteins.
J. Am. Chem. Soc. (1993) 115: 4849-4858.

Wladia Viviani, Jean Louis Rivail, András Perczel, Imre G. Csizmadia:
Peptide models. 3. Conformational potential-energy hypersurface of formyl-L-valinamide.
J. Am. Chem. Soc. (1993) 115: 8321-8329.

András Perczel, János G. Ángyan, Márton Kajtár, Wladia Viviani, Jean Louis Rivail, John Frank Marcoccia, Imre G. Csizmadia
Peptide models. 1. Topology of selected peptide conformational potential-energy surfaces (Glycine and alanine derivatives).
J. Am. Chem. Soc. (1991) 113: 6256-6265.

Conformational dependence of side-chain protonation properties of α-amino acids

Protonation and deprotonation of side chain of certain amino acids in proteins and peptides are important in many catalytic, di- or polymerization processes as well as 3D-structure changes. Both, geometries acquired from muldidimensional conformational analysis (MDCA) or constrained geometries mimicking the conformation in protein can be used as structures for PA and pK_a calculations.

Publications
Péter Hudáky and András Perczel:
Conformation dependence of pK_a: ab initio and DFT investigation of histidine
J. Phys. Chem. A (2004) 108(29):6195-6205.
[abstract] [supporting information]

Chemical shift calculations of α-amino acids and peptides

Protein/peptide NMR structure determination could be speed up by using chemical shift information to establish backbone folding units. Especially, two- and three-dimensional NMR spectra can be useful in this respect. Our results suggest that such methods are viable because relevant correlations between backbone fold and ¹Hα and ¹³Cα chemical shift values can be found. Our calculation methods comprise the GIAO-RHF formalism with the 6-31+G* and TZ2P basis sets.

Publications

Péter Hudáky and András Perczel:
Toward direct determination of conformations of protein building units from multidimensional NMR experiments VI. Chemical shift analysis of His to gain 3D structure and protonation state information
J. Comput. Chem. (2005) 26:1307-1317.
[abstract]

András Czajlik and András Perczel:
Peptide Models XXXII. Computed chemical shift analysis of penetratin fragments
J. Mol. Struct. (THEOCHEM) (2004) 675(1-3): 129-139.
[abstract]

András Perczel, Anna K. Füzéry, Attila G. Császár:
Toward direct determination of conformations of protein building units from multidimensional NMR experiments. V. NMR chemical shielding analysis of N-formyl-serinamide, a model for polar side-chain containing peptides
J. Comput. Chem. (2003) 24(10): 1157-1171.
[abstract]

Eszter Czinki, Attila G. Császár and András Perczel:
A theoretical case study of type I and type II β-turns
Chem Eur J (2003) 9(5): 1182-1191
[abstract]

András Perczel, Attila G. Császár:
Toward direct determination of conformations of protein building units from multidimensional NMR experiments III-A theoretical case study of For-L-Phe-NH2.
Eur. Phys. J. (2002) D20: 513-530.

András Perczel, Attila G. Császár:
Toward direct determination of conformations of protein building units from multidimensional NMR experiments part II: A theoretical case study of formyl-L-valine amide.
Chem Eur J (2001) 7: 1069-1083.
[abstract]

András Perczel, Attila G. Császár:
Toward direct determination of conformations of protein building units from multidimensional NMR experiments I. A theoretical case study of For-Gly-NH2 and For-L-Ala-NH2.
J. Comput. Chem. (2000) 21: 882-900.
[abstract]

Conformational studies of β-amino acids and peptides

One of the main quetsions about the origin of life on Earth is why α-amino acids are preferred over β-amino acids in proteins. An answer to this question can be obtained by investigating the conformational preferences of β-amino acids. Moreover, β-peptides are increasingly used in peptide derivatives for various purposes including reduction of degradation in biological systems. Structures of peptides built up from β-amino acid resuidues are studied by experimental methods. We aim to explore the conformational behaviors of such peptides. Our results show reasonable agreement with experimental data.

Publications

Tamás Beke, Imre G. Csizmadia and András Perczel:
Theoretical study on tertiary structural elements of β-peptides: Nanotubes formed from parallel-sheet-derived a ssemblies of β-peptides
J. Am. Chem. Soc. (2006) 128:5158-5167.
[abstract]

Tamás Beke, András Czajlik, Imre G. Csizmadia and András Perczel:
Determining suitable lego-structures to estimate stability of larger nanostructures using computational method s
Phys. Biol. (2006) 3:S26-S39.
[abstract]

Tamás Beke, Csaba Somlai and András Perczel:
Toward a rational design of β-peptide structures.
J. Comput. Chem. (2006) 27:20-38.
[abstract]

András Láng, Anna K. Füzéry, Tamás Beke, Péter Hudáky and András Perczel:
Potential Energy Curves, Surfaces and Hypersurfaces. A model to follow and understand the conformational transformations in amino acids.
J. Mol. Struct. (THEOCHEM) (2004) 675(1-3): 163-175.
[abstract]

Tamás Beke, Imre G. Csizmadia, András Perczel:
On the flexibility of β-peptides
J. Comput. Chem. (2004) 25:285-307.
[abstract]