Hybrid SCC-DFTB/molecular mechanical studies of H-bonded systems and ofN-acetyl-(L-Ala)nN?-methylamide helices in water solution

A hybrid quantum mechanical (QM) and molecular mechanical (MM) approach has been developed and used to study the aqueous solvation effect on biological systems. The self-consistent charge density functional tight-binding (SCC-DFTB) method is employed to perform the quantum mechanical calculations in the QM part, while the AMBER 4.1 force field is used to perform the molecular mechanical calculations in the MM part. The coupling terms between these two parts include electrostatic and van der Waal's interactions. As a test of feasibility, this approach has been first applied to some small systems H-bonded with water molecule(s), and very good agreement with the ab initio results has been achieved. The hybrid potential was then used to investigate the solvation effect on the capped (L-Ala)n helices with n=4, 5, 8 and 11. (L-Ala)n was treated with the SCC-DFTB method and the water molecules with the TIP3P water model. It has been shown that, in gas phase, the α helices of (L-Ala)n are less stable than the corresponding 310 helices. In water solution, however, the α helices are stabilized and, compared with 310 helices, the α helices have stronger charge–charge interactions with the surrounding water molecules. This may be explained by the larger dipole moment of α helices in aqueous solution, which will influence and organize the orientations of the surrounding water molecules. © 2000 John Wiley & Sons, Inc. Int J Quant Chem 78: 459–479, 2000

[1]  W. Thiel,et al.  Hybrid Models for Combined Quantum Mechanical and Molecular Mechanical Approaches , 1996 .

[2]  G. Millhauser,et al.  Short alanine-based peptides may form 310-helices and not α-helices in aqueous solution , 1992, Nature.

[3]  J. Thornton,et al.  Helix geometry in proteins. , 1988, Journal of molecular biology.

[4]  William L. Jorgensen,et al.  Molecular dynamics and Monte Carlo simulations favor the .alpha.-helical form for alanine-based peptides in water , 1993 .

[5]  Garland R. Marshall,et al.  Free energy profile of a 310- to .alpha.-helical transition of an oligopeptide in various solvents , 1993 .

[6]  W. Harrison,et al.  Elementary prediction of linear combination of atomic orbitals matrix elements , 1979 .

[7]  M. Bodkin,et al.  Competing interactions contributing to α‐helical stability in aqueous solution , 1995 .

[8]  U. Singh,et al.  A combined ab initio quantum mechanical and molecular mechanical method for carrying out simulations on complex molecular systems: Applications to the CH3Cl + Cl− exchange reaction and gas phase protonation of polyethers , 1986 .

[9]  T. R. Dyke,et al.  Partially deuterated water dimers: Microwave spectra and structure , 1980 .

[10]  S. Sung.  Folding simulations of alanine-based peptides with lysine residues. , 1995, Biophysical journal.

[11]  Foulkes,et al.  Tight-binding models and density-functional theory. , 1989, Physical review. B, Condensed matter.

[12]  S. Suhai,et al.  DENSITY FUNCTIONAL STUDIES ON N-METHYLACETAMIDE-WATER COMPLEXES , 1996 .

[13]  J. Hermans,et al.  310 HELIX VERSUS ALPHA -HELIX : A MOLECULAR DYNAMICS STUDY OF CONFORMATIONAL PREFERENCES OF AIB AND ALANINE , 1994 .

[14]  C. Toniolo,et al.  Critical main-chain length for conformational conversion from 3(10)-helix to alpha-helix in polypeptides. , 1990, Journal of biomolecular structure & dynamics.

[15]  Charles L. Brooks,et al.  Conformational equilibrium in the alanine dipeptide in the gas phase and aqueous solution : a comparison of theoretical results , 1992 .

[16]  J Hermans,et al.  Microfolding: Conformational probability map for the alanine dipeptide in water from molecular dynamics simulations , 1988, Proteins.

[17]  T. Dyke,et al.  Rotational spectra and structure of the ammonia–water complex , 1985 .

[18]  G. Millhauser,et al.  Increasing sequence length favors alpha-helix over 3(10)-helix in alanine-based peptides: evidence for a length-dependent structural transition. , 1993, Biochemistry.

[19]  I. Gould,et al.  Mechanism and transition state structure for papain catalysed amide hydrolysis, using a hybrid QM/MM potential , 1996 .

[20]  R. J. Boyd,et al.  A hybrid quantum mechanical force field molecular dynamics simulation of liquid methanol: Vibrational frequency shifts as a probe of the quantum mechanical/molecular mechanical coupling , 1996 .

[21]  C. Stout,et al.  The structure of aconitase , 1989, Proteins.

[22]  Lennart Nilsson,et al.  Molecular dynamics simulation of galanin in aqueous and nonaqueous solution , 1992 .

[23]  Garland R. Marshall,et al.  α/310‐Helix transitions in α‐methylalanine homopeptides: Conformational transition pathway and potential of mean force , 1994 .

[24]  W. L. Jorgensen.  Quantum and statistical mechanical studies of liquids. 10. Transferable intermolecular potential functions for water, alcohols, and ethers. Application to liquid water , 2002 .

[25]  A. Mark,et al.  The effect of environment on the stability of an integral membrane helix: molecular dynamics simulations of surfactant protein C in chloroform, methanol and water. , 1995, Journal of molecular biology.

[26]  W. J. Stevens,et al.  Abinitio study of the hydrogen bonding interactions of formamide with water and methanol , 1986 .

[27]  G. Millhauser,et al.  Estimating the relative populations of 3(10)-helix and alpha-helix in Ala-rich peptides: a hydrogen exchange and high field NMR study. , 1997, Journal of molecular biology.

[28]  E. Coitiño,et al.  Theoretical studies of hydrogen-bonded complexes using semiempirical methods , 1990 .

[29]  D. Millen,et al.  Hydrogen bonding in the gas phase. Part 5.—Infrared spectroscopic investigation of O—H ⋯ N complexes formed by water: ammonia monohydrate and amine and pyridine monohydrates , 1977 .

[30]  J Tirado-Rives,et al.  Molecular dynamics simulations of the unfolding of an alpha-helical analogue of ribonuclease A S-peptide in water. , 1991, Biochemistry.

[31]  C. Brooks,et al.  Thermodynamics and mechanism of alpha helix initiation in alanine and valine peptides. , 1991, Biochemistry.

[32]  Charles L. Brooks,et al.  Dielectric Continuum Models for Hydration Effects on Peptide Conformational Transitions , 1996 .

[33]  B. Montgomery Pettitt,et al.  Conformational free energy of hydration for the alanine dipeptide: Thermodynamic analysis , 1988 .

[34]  Sándor Suhai,et al.  Theoretical Study of Aqueous N-Acetyl-l-alanine N‘-Methylamide: Structures and Raman, VCD, and ROA Spectra , 1998 .

[35]  Sándor Suhai,et al.  N-Acetyl-L-alanine N'-methylamide: a density functional analysis of the vibrational absorption and vibrational circular dichroism spectra , 1996 .

[36]  Ian R. Gould,et al.  A quantum Mechanical Investigation of the Conformational Energetics of the Alanine and Glycine Dipeptides in the Gas Phase and in Aqueous Solution , 1994 .

[37]  F. J. Luque,et al.  Helical preferences of alanine, glycine, and aminoisobutyric homopeptides , 1997, Proteins.

[38]  A. Tortschanoff,et al.  THE CONVOLUTION PROBLEM IN COIN SPECTROSCOPY , 1999 .

[39]  D. Ollis,et al.  Refined structure of dienelactone hydrolase at 1.8 A. , 1990, Journal of molecular biology.

[40]  S. Suhai.  Density Functional Studies of the Hydrogen-Bonded Network in an Infinite Water Polymer , 1995 .

[41]  Feliu Maseras,et al.  IMOMM: A new integrated ab initio + molecular mechanics geometry optimization scheme of equilibrium structures and transition states , 1995, J. Comput. Chem..

[42]  G. Millhauser.  Views of helical peptides: a proposal for the position of 3(10)-helix along the thermodynamic folding pathway. , 1995, Biochemistry.

[43]  Larry A. Curtiss,et al.  Studies of molecular association in H2O and D2O vapors by measurement of thermal conductivity , 1979 .

[44]  C L Brooks,et al.  A microscopic view of helix propagation: N and C-terminal helix growth in alanine helices. , 1996, Journal of molecular biology.

[45]  Dennis R. Salahub,et al.  A combined density functional and molecular dynamics simulation of a quantum water molecule in aqueous solution , 1994 .

[46]  M. Levitt,et al.  Theoretical studies of enzymic reactions: dielectric, electrostatic and steric stabilization of the carbonium ion in the reaction of lysozyme. , 1976, Journal of molecular biology.

[47]  P. Fowler,et al.  Velocity-dependent property surfaces and the theory of vibrational circular dichroism , 1987 .

[48]  P. V. van Duijnen,et al.  Cooperative effects in α‐helices: An ab initio molecular‐orbital study , 1982 .

[49]  Brian J. Smith,et al.  Transition structures for the interchange of hydrogen atoms within the water dimer , 1990 .

[50]  Jean-Louis Rivail,et al.  HYBRID CLASSICAL QUANTUM FORCE FIELD FOR MODELING VERY LARGE MOLECULES , 1996 .

[51]  J. C. Slater,et al.  Simplified LCAO Method for the Periodic Potential Problem , 1954 .

[52]  M. E. Karpen,et al.  Differences in the amino acid distributions of 310‐helices and α‐helices , 1992 .

[53]  D. Hohl,et al.  Density Functional Theory and Biomolecules: A Study of Glycine, Alanine, and Their Oligopeptides , 1998 .

[54]  J. Mavri,et al.  Calculations by the semi-ab initio method SAM1 on some hydrogen-bonded systems , 1997 .

[55]  Tai-Sung Lee,et al.  A pseudobond approach to combining quantum mechanical and molecular mechanical methods , 1999 .

[56]  J. A. Odutola,et al.  Water dimer tunneling states with K=0 , 1988 .

[57]  William L. Jorgensen,et al.  Ab initio and Monte Carlo calculations for a nucleophilic addition reaction in the gas phase and in aqueous solution , 1986 .

[58]  S Suhai,et al.  QM/MM study of the active site of free papain and of the NMA-papain complex. , 1999, Journal of biomolecular structure & dynamics.

[59]  John S. Muenter,et al.  THE STRUCTURE OF WATER DIMER FROM MOLECULAR BEAM ELECTRIC RESONANCE SPECTROSCOPY: PARTIALLY DEUTERATED DIMERS , 1977 .

[60]  R. Ornstein,et al.  A combined density functional theory/molecular mechanics formalism and its application to small water clusters , 1997 .

[61]  S. Scheiner,et al.  Structure, energetics, and vibrational spectrum of H3N..HOH. , 1990 .

[62]  H. Böhm,et al.  Interaction potentials for alkali ion–rare gas and halogen ion–rare gas systems , 1988 .

[63]  Andrey A. Bliznyuk,et al.  A combined quantum chemical/molecular mechanical study of hydrogen-bonded systems , 1992 .

[64]  R. Fine,et al.  A CFF 91-based Continuum Solvation Model: Solvation Free Energies of Small Organic Molecules and Conformations of the Alanine Dipeptide in Solution , 1994 .

[65]  Harrison.  Overlap interactions and bonding in ionic solids. , 1986, Physical review. B, Condensed matter.

[66]  Sándor Suhai,et al.  Self-consistent-charge density-functional tight-binding method for simulations of complex materials properties , 1998 .

[67]  N R Kallenbach,et al.  Side chain contributions to the stability of alpha-helical structure in peptides. , 1990, Science.

[68]  Kenneth M. Merz,et al.  An examination of a density functional/molecular mechanical coupled potential , 1995, J. Comput. Chem..

[69]  James Andrew McCammon,et al.  Molecular dynamics simulation with a continuum electrostatic model of the solvent , 1995, J. Comput. Chem..

[70]  David A. Case,et al.  Unfolding of an α‐helix in water , 1991 .

[71]  R. L. Baldwin,et al.  Helix propensities of the amino acids measured in alanine‐based peptides without helix‐stabilizing side‐chain interactions , 1994, Protein science : a publication of the Protein Society.

[72]  K. Jalkanen,et al.  Solution-Phase Conformations of N-Acetyl-N‘-methyl-l-alaninamide from Vibrational Raman Optical Activity , 1996 .

[73]  Seifert,et al.  Construction of tight-binding-like potentials on the basis of density-functional theory: Application to carbon. , 1995, Physical review. B, Condensed matter.

[74]  I. Karle,et al.  Structural characteristics of alpha-helical peptide molecules containing Aib residues. , 1990, Biochemistry.

[75]  M. Karplus,et al.  A combined quantum mechanical and molecular mechanical potential for molecular dynamics simulations , 1990 .

[76]  M Levitt,et al.  Molecular dynamics simulations of helix denaturation. , 1992, Journal of molecular biology.

[77]  P. Stephens.  Theory of vibrational circular dichroism , 1985 .