Structures of the Peptide–Water Complexes Studied by the Hybrid Quantum Mechanical—Molecular Mechanical (QM/MM) Technique

Applications of a new approach to the hybrid quantum mechanical and molecular mechanical (QM/MM) theory based on the effective fragment potential technique to calculations of the structures of the peptide—water complexes are described. Our approach assumes that the MM subsystem is viewed as a flexible composition of effective fragments, while fragment–fragment interactions are replaced by MM force fields. In this work, the QM subsystem is composed of water molecules and the MM part refers to peptides. Different isomers of the hydrogen-bonded complex of the dipeptide N-acetyl-L-alanine N-methylamide (AAMA) with four water molecules are considered, and the results of QM/MM calculations are compared to experimental data and to the results of the density functional theory (DFT) treatment. The properties of water chains inside polypeptide tubes, modeling proton wires inside ionic channels, are described.     

Nonuniform charge scaling (NUCS): a practical approximation of solvent electrostatic screening in proteins

In molecular mechanics calculations, electrostatic interactions between chemical groups are usually represented by a Coulomb potential between the partial atomic charges of the groups. In aqueous solution these interactions are modified by the polarizable solvent. Although the electrostatic effects of the polarized solvent on the protein are well described by the Poisson--Boltzmann equation, its numerical solution is computationally expensive for large molecules such as proteins. The procedure of nonuniform charge scaling (NUCS) is a pragmatic approach to implicit solvation that approximates the solvent screening effect by individually scaling the partial charges on the explicit atoms of the macromolecule so as to reproduce electrostatic interaction energies obtained from an initial Poisson--Boltzmann analysis. Once the screening factors have been determined for a protein the scaled charges can be easily used in any molecular mechanics program that implements a Coulomb term. The approach is particularly suitable for minimization-based simulations, such as normal mode analysis, certain conformational reaction path or ligand binding techniques for which bulk solvent cannot be included explicitly, and for combined quantum mechanical/molecular mechanical calculations when the interface to more elaborate continuum solvent models is lacking. The method is illustrated using reaction path calculations of the Tyr 35 ring flip in the bovine pancreatic trypsin inhibitor.     

Generalized energy-based fragmentation approach for computing the ground-state energies and properties of large molecules

We present a generalized energy-based fragmentation (GEBF) approach for approximately predicting the ground-state energies and molecular properties of large molecules, especially those charged and polar molecules. In this approach, the total energy (or properties) of a large molecule can be approximately obtained from energy (or properties) calculations on various small subsystems, each of which is constructed to contain a certain fragment and its local surroundings within a given distance. In the quantum chemistry calculation of a given subsystem, those distant atoms (outside this subsystem) are modeled as background point charges at the corresponding nuclear centers. This treatment allows long-range electrostatic interaction and polarization effects between distant fragments to be taken into account approximately, which are very important for polar and charged molecules. We also propose a new fragmentation scheme for constructing subsystems. Our test calculations at the Hartree-Fock and second-order M?ller-Plesser perturbation theory levels demonstrate that the approach could yield satisfactory ground-state energies, the dipole moments, and static polarizabilities for polar and charged molecules such as water clusters and proteins.     

Ab initio quality properties for macromolecules using the ADMA approach

We describe new developments of an earlier linear scaling algorithm for ab initio quality macromolecular property calculations based on the adjustable density matrix assembler (ADMA) approach. In this approach, a large molecule is divided into fuzzy fragments, for which quantum chemical calculations can easily be done using moderate-size "parent molecules" that contain all the local interactions within a selected distance. If greater accuracy is required, a larger distance is chosen. With the present extension of this approximation, properties of the large molecules, like the electron density, the electrostatic potential, dipole moments, partial charges, and the Hartree-Fock energy are calculated. The accuracy of the method is demonstrated with test cases of medium size by comparing the ADMA results with direct quantum chemical calculations.     

Properties of liquid crystal molecules from first principles computer simulation

We explore the valence charge distribution, equilibrium geometry and harmonic force fields of the 4-pentyl-4-cyanobiphenyl (5CB) molecule and the benzene (C6H6) molecule, which provides an important mesogenic fragment, using first principles techniques adapted from large scale electronic structure calculations of periodic solids. We present for the first time accurate structural data for the isolated 5CB molecule and observe subtle broken symmetries relative to the constituent mesogenic fragments. The dynamic properties of these molecules are determined by diagonalization of dynamical matrices, the elements of which are obtained directly from quantum mechanical Hellmann-Feynman forces. Results for both molecules are in excellent agreement with available spectroscopic data, and for benzene are comparable to the most accurate quantum chemistry calculations to date. For 5CB we also present values for the molecular dipole and quadrupole moments.     

Continuum treatment of electronic polarization effect

A continuum treatment of electronic polarization has been explored for in molecular mechanics simulations in implicit solvents. The dielectric constant for molecule interior is the only parameter in the continuum polarizable model. A value of 4 is found to yield optimal agreement with high-level ab initio quantum mechanical calculations for the tested molecular systems. Interestingly, its performance is not sensitive to the definition of molecular volume, in which the continuum electronic polarization is defined. In this model, quantum mechanical electrostatic field in different dielectric environments from vacuum, low-dielectric organic solvent, and water can be used simultaneously in atomic charge fitting to achieve consistent treatment of electrostatic interactions. The tests show that a single set of atomic charges can be used consistently in different dielectric environments and different molecular conformations, and the atomic charges transfer well from training monomers to tested dimers. The preliminary study gives us the hope of developing a continuum polarizable force field for more consistent simulations of proteins and nucleic acids in implicit solvents.     

Specific interactions and binding free energies between thermolysin and dipeptides: molecular simulations combined with ab initio molecular orbital and classical vibrational analysis

Thermolysin (TLN) is a metalloprotease widely used as a nonspecific protease for sequencing peptide and synthesizing many useful chemical compounds by the chemical industry. It was experimentally shown that the activity and functions of TLN are inhibited by the binding of many types of amino acid dipeptides. However, the binding mechanisms between TLN and dipeptides have not been clarified at the atomic and electronic levels. In this study, we investigated the binding mechanisms between TLN and four dipeptides. Specific interactions and binding free energies (BFEs) between TLN and the dipeptides were calculated using molecular simulations based on classical molecular dynamics and ab initio fragment molecular orbital (FMO) methods. The molecular systems were embedded in solvating water molecules during calculations. The calculated BFEs were qualitatively consistent with the trend of the experimentally observed inhibition of TLN activity by binding of the dipeptides. In addition, the specific interactions between the dipeptides and each amino acid residue of TLN or solvating water molecules were elucidated by the FMO calculations.     

A molecular mechanics force field for lignin

A CHARMM molecular mechanics force field for lignin is derived. Parameterization is based on reproducing quantum mechanical data of model compounds. Partial atomic charges are derived using the RESP electrostatic potential fitting method supplemented by the examination of methoxybenzene:water interactions. Dihedral parameters are optimized by fitting to critical rotational potentials and bonded parameters are obtained by optimizing vibrational frequencies and normal modes. Finally, the force field is validated by performing a molecular dynamics simulation of a crystal of a lignin fragment molecule and comparing simulation-derived structural features with experimental results. Together with the existing force field for polysaccharides, this lignin force field will enable full simulations of lignocellulose.     

Effect of interprotein polarization on protein–protein binding energy

Molecular dynamics simulation in explicit water for the binding of the benchmark barnase‐barstar complex was carried out to investigate the effect polarization of interprotein hydrogen bonds on its binding free energy. Our study is based on the AMBER force field but with polarized atomic charges derived from fragment quantum mechanical calculation for the protein complex. The quantum‐derived atomic charges include the effect of polarization of interprotein hydrogen bonds, which was absent in the standard force fields that were used in previous theoretical calculations of barnase‐barstar binding energy. This study shows that this polarization effect impacts both the static (electronic) and dynamic interprotein electrostatic interactions and significantly lowers the free energy of the barnase‐barstar complex. © 2012 Wiley Periodicals, Inc.     

The coordination of uranyl in water: a combined quantum chemical and molecular simulation study

The coordination environment of uranyl in water has been studied using a combined quantum mechanical and molecular dynamics approach. Multiconfigurational wave function calculations have been performed to generate pair potentials between uranyl and water. The quantum chemically determined energies have been used to fit parameters in a polarizable force field with an added charge transfer term. Molecular dynamics simulations have been performed for the uranyl ion and up to 400 water molecules. The results show a uranyl ion with five water molecules coordinated in the equatorial plane. The U-O(H(2)O) distance is 2.40 A, which is close to the experimental estimates. A second coordination shell starts at about 4.7 A from the uranium atom. No hydrogen bonding is found between the uranyl oxygens and water. Exchange of waters between the first and second solvation shell is found to occur through a path intermediate between association and interchange. This is the first fully ab initio determination of the solvation of the uranyl ion in water.     

Theoretical prediction of spectral and optical properties of bacteriochlorophylls in thermally disordered LH2 antenna complexes

A general approach for calculating spectral and optical properties of pigment-protein complexes of known atomic structure is presented. The method, that combines molecular dynamics simulations, quantum chemistry calculations, and statistical mechanical modeling, is demonstrated by calculating the absorption and circular dichroism spectra of the B800-B850 bacteriochlorophylls of the LH2 antenna complex from Rs. molischianum at room temperature. The calculated spectra are found to be in good agreement with the available experimental results. The calculations reveal that the broadening of the B800 band is mainly caused by the interactions with the polar protein environment, while the broadening of the B850 band is due to the excitonic interactions. Since it contains no fitting parameters, in principle, the proposed method can be used to predict optical spectra of arbitrary pigment-protein complexes of known structure.     

Finding MOFs for highly selective CO2/N2 adsorption using materials screening based on efficient assignment of atomic point charges

Electrostatic interactions are a critical factor in the adsorption of quadrupolar species such as CO(2) and N(2) in metal-organic frameworks (MOFs) and other nanoporous materials. We show how a version of the semiempirical charge equilibration method suitable for periodic materials can be used to efficiently assign charges and allow molecular simulations for a large number of MOFs. This approach is illustrated by simulating CO(2) and N(2) adsorption in ~500 MOFs; this is the largest set of structures for which this information has been reported to date. For materials predicted by our calculations to have promising adsorption selectivities, we performed more detailed calculations in which accurate quantum chemistry methods were used to assign atomic point charges, and molecular simulations were used to assess molecular diffusivities and binary adsorption isotherms. Our results identify two MOFs, experimentally known to be stable upon solvent removal, that are predicted to show no diffusion limitations for adsorbed molecules and extremely high CO(2)/N(2) adsorption selectivities for CO(2) adsorption from dry air and from gas mixtures typical of dry flue gas.     

Toward a new approach for determination of solute's charge distribution to analyze interatomic electrostatic interactions in quantum mechanical/molecular mechanical simulations

We present an alternative approach to determine "density-dependent property"-derived charges for molecules in the condensed phase. In the case of a solution, it is essential to take into consideration the electron polarization of molecules in the active site of this system. The solute and solvent molecules in this site have to be described by a quantum mechanical technique and the others are allowed to be treated by a molecular mechanical method (QM/MM scheme). For calculations based on this scheme, using the forces and interaction energy as density-dependent property our charges from interaction energy and forces (CHIEF) approach can provide the atom-centered charges on the solute atoms. These charges reproduce well the electrostatic potentials around the solvent molecules and present properly the picture of the electron density of the QM subsystem in the solution system. Thus, the CHIEF charges can be considered as the atomic charges under the conditions of the QM/MM simulation, and then enable one to analyze electrostatic interactions between atoms in the QM and MM regions. This approach would give a view of the QM nuclei and electrons different from the conventional methods.     

Thermodynamic contributions of the ordered water molecule in HIV-1 protease

Binding between biomolecules is usually accompanied by the formation of direct interactions with displacement of water from the binding sites. In some cases, however, the interactions are mediated by ordered water molecules, whose effect on binding affinity and the other thermodynamic functions is unclear. In this work, we compute the contribution of one such water molecule, the strongly bound water molecule at the binding site of HIV-1 protease, to the thermodynamic properties using statistical mechanical formulas for the energy and entropy. The requisite correlation functions are obtained by molecular dynamics simulations. We find that the entropic penalty of ordering is large but is outweighed by the favorable water-protein interactions. We also find a large negative contribution from this water molecule to the heat capacity. This approach could be useful in rational drug design by estimating which bound water molecules would be most favorable to displace.     

Proton conduction along a chain of water molecules. Development of a linear model and quantum dynamical investigations using the multiconfiguration time-dependent Hartree method

Proton transfer along a chain of water molecules is discussed. A linear model for such a chain is developed and its parameters are determined by comparison to quantum chemistry calculations. Fully quantum mechanical dynamical simulations on the translocation process are performed for different chain lengths, with up to five water molecules. We found that tunneling is important for the proton-transfer process. Furthermore, translocation is accomplished through a strongly correlated motion involving both hydrogen and oxygen atoms. An approximate treatment, which limits or even neglects this correlation, may lead to severely incorrect results.     

Multilayer adsorption of water at a rutile TiO2)(110) surface: towards a realistic modeling by molecular dynamics

We present a model combining ab initio concepts and molecular dynamics simulations for a more realistic treatment of complex adsorption processes. The energy, distance, and orientation of water molecules adsorbed on stoichiometric and reduced rutile TiO(2)(110) surfaces at 140 K are studied via constant temperature molecular dynamics simulations. From ab initio calculations relaxed atomic geometries for the surface and the most probable adsorption sites were derived. The study comprises (i) large two-dimensional surface supercells, providing a realistically low concentration of surface oxygen defects, and (ii) a water coverage sufficiently large to model the onset of the growth of a bulk phase of water on the surface. By our combined approach the influence of both, the metal oxide surface, below, and the bulk water phase, above, on the water molecules forming the interface between the TiO(2) surface and the water bulk layer is taken into account. The good agreement of calculated adsorption energies with experimental temperature programmed desorption spectra demonstrates the validity of our model.     

Elastic properties of single amylose chains in water: a quantum mechanical and AFM study

Recent single-molecule atomic force microscopy (AFM) experiments have revealed that some polysaccharides display large deviations from force-extension relationships of other polymers which typically behave as simple entropic springs. However, the mechanism of these deviations has not been fully elucidated. Here we report the use of novel quantum mechanical methodologies, the divide-and-conquer linear scaling approach and the self-consistent charge density functional-based tight binding (SCC-DFTB) method, to unravel the mechanism of the extensibility of the polysaccharide amylose, which in water displays particularly large deviations from the simple entropic elasticity. We studied the deformations of maltose, a building block of amylose, both in a vacuum and in solution. To simulate the deformations in solution, the TIP3P molecular mechanical model is used to model the solvent water, and the SCC-DFTB method is used to model the solute. The interactions between the solute and water are treated by the combined quantum mechanical and molecular mechanical approach. We find that water significantly affects the mechanical properties of maltose. Furthermore, we performed two nanosecond-scale steered molecular dynamics simulations for single amylose chains composed of 10 glucopyranose rings in solution. Our SCC-DFTB/MM simulations reproduce the experimentally measured force-extension curve, and we find that the force-induced chair-to-boat transitions of glucopyranose rings are responsible for the characteristic plateau in the force-extension curve of amylose. In addition, we performed single-molecule AFM measurements on carboxymethyl amylose, and we found that, in contrast to the results of an earlier work by others, these side groups do not significantly affect amylose elasticity. By combining our experimental and modeling results, we conclude that the nonentropic elastic behavior of amylose is governed by the mechanics of pyranose rings themselves and their force-induced conformational transitions.     

Computational analysis of the proton translocation from Asp96 to schiff base in bacteriorhodopsin

The potential energy change during the M --> N process in bacteriorhodopsin has been evaluated by ab initio quantum chemical and advanced quantum chemical calculations following molecular dynamics (MD) simulations. Many previous experimental studies have suggested that the proton transfer from Asp96 to the Schiff base occurs under the following two conditions: (1) the hydrogen bond between Thr46 and Asp96 breaks and Thr46 is detached from Asp96 and (2) a stable chain of four water molecules spans an area from Asp96 --> Schiff base. In this work, we successfully reproduced the proton-transfer process occurring under these two conditions by molecular dynamics and quantum chemical calculations. The quantum chemical computation revealed that the proton transfer from Asp96 to Shiff base occurs in two-step reactions via an intermediate in which an H(3)O(+) appears around Ala215. The activation energy for the proton transfer in the first reaction was calculated to be 9.7 kcal/mol, which enables fast and efficient proton pump action. Further QM/MM (quantum mechanical/molecular mechanical) and FMO (fragment molecular orbital) calculations revealed that the potential energy change during the proton transfer is tightly regulated by the composition and the geometry of the surrounding amino acid residues of bacteriorhodopsin. Here, we report in detail the Asp96 --> Schiff base proton translocation mechanism of bacteriorhodopsin. Additionally, we discuss the effectiveness of combining quantum chemical calculations with truncated cluster models followed by advanced quantum chemical calculations applied to a whole protein to elucidate its reaction mechanism.