The nature of intermolecular interactions between aromatic amino acid residues

The nature of intermolecular interactions between aromatic amino acid residues has been investigated by a combination of molecular dynamics and ab initio methods. The potential energy surface of various interacting pairs, including tryptophan, phenilalanine, and tyrosine, was scanned for determining all the relevant local minima by a combined molecular dynamics and conjugate gradient methodology with the AMBER force field. For each of these minima, single-point correlated ab initio calculations of the binding energy were performed. The agreement between empirical force field and ab initio binding energies of the minimum energy structures is excellent. Aromatic-aromatic interactions can be rationalized on the basis of electrostatic and van der Waals interactions, whereas charge transfer or polarization phenomena are small for all intermolecular complexes and, particularly, for stacked structures. Proteins 2002;48:117-125.     

Post Hartree-Fock studies of the canonical Watson-Crick DNA base pairs: molecular structure and the nature of stability

Gas-phase gradient optimization was carried out on the canonical Watson-Crick DNA base pairs using the second-order M?ller-Plesset perturbation method at the 6-31G(d) and 6-31G(d,p) basis sets. It is detected that full geometry optimization at the MP2 level leads to an intrinsically nonplanar propeller-twisted and buckled geometry of G-C and A-T base pairs; while HF and DFT methods predict perfect planar or almost planar geometry of the base pairs. Supposedly the nonplanarity of the pairs is caused by pyramidalization of the amino nitrogen atoms, which is underestimated by the HF and DFT methods. This justifies the importance of geometry optimization at the MP2 level for obtaining reliable prediction of the charge distribution, molecular dipole moments and geometrical structure of the base pairs. The Morokuma-Kitaura and the Reduced Variational Space methods of the decomposition for molecular HF interaction energies were used for investigation of the hydrogen bonding in the Watson-Crick base pairs. It is shown that the HF stability of the hydrogen-bonded DNA base pairs originates mainly from electrostatic interactions. At the same time, the calculated magnitude of the second order intramolecular correlation correction to the Coulomb energy showed that electron correlation reduces the contribution of the electrostatic term to the attractive interaction for the A-T and G-C base pairs. Polarization, charge transfer and dispersion interactions also make considerable contribution to the attraction energy of bases.     

Quantum mechanical study of bases interactions in various associates in atomic dipole approximation

Expressions for the various components of the long-range interaction energy of any number of molecules are obtained by the perturbation theory method in atomic dipole approximation. These expressions are used for the study of base interaction nature in coplanar pairs and stacked dimers formed of neighbouring Watson-Crick pairs. Bases wave functions are computed by the CNDO-CI method. The in-plane interactions are shown to give the dominant contribution into the DNA stabilization energy in vacuum. The estimations performed for the solvent effect on intermolecular interaction energy allowed one to draw a conclusion about the decisive role of hydrophobic interactions in a base stacking.     

Charge calculations in molecular mechanics 6: the calculation of partial atomic charges in nucleic acid bases and the electrostatic contribution to DNA base pairing.

A previously described scheme for the direct calculation of the partial atomic charges in molecules (CHARGE2) is applied to the nucleic acid bases. It is shown that inclusion of the omega-technique for the calculation of HMO derived pi charges is of particular importance for these highly polar systems. The molecular dipole moments obtained for the resulting charges are in very good agreement with the observed values for a variety of substituted purine and pyrimidine bases. The partial atomic charges for cytosine, thymine, guanine and adenine (as the 1-methyl and 9-methyl forms) are given and compared with values calculated by a variety of molecular orbital and empirical schemes. All the schemes reproduce the same general trends, with the possible exception of those calculated by the Del Re method, though the charges given by Kollman are in general somewhat larger than the others. The electrostatic contribution to the Watson-Crick base pair interaction energies are calculated using these partial atomic charges. The electrostatic contributions obtained from the M.O. derived atomic charges are less than half the observed values, as are those obtained by the Gasteiger method. The electrostatic contributions calculated from the CHARGE2 atomic charges and those of Kollman are in reasonable agreement with the observed values. The influence of a distant-dependent dielectric constant is examined, but no clear pattern emerges.     

Post Hartree-Fock Studies of the Canonical Watson-Crick DNA Base Pairs: Molecular Structure and the Nature of Stability

Abstract

Gas-phase gradient optimization was carried out on the canonical Watson-Crick DNA base pairs using the second-order Møller-Plesset perturbation method at the 6–31G(d) and 6- 31G(d,p) basis sets. It is detected that full geometry optimization at the MP2 level leads to an intrinsically nonplanar propeller-twisted and buckled geometry of G-C and A-T base pairs; while HF and DFT methods predict perfect planar or almost planar geometry of the base pairs. Supposedly the nonplanarity of the pairs is caused by pyramidalization of the amino nitrogen atoms, which is underestimated by the HF and DFT methods. This justifies the importance of geometry optimization at the MP2 level for obtaining reliable prediction of the charge distribution, molecular dipole moments and geometrical structure of the base pairs. The Morokuma-Kitaura and the Reduced Variational Space methods of the decomposition for molecular HF interaction energies were used for investigation of the hydrogen bonding in the Watson-Crick base pairs. It is shown that the HF stability of the hydrogen-bonded DNA base pairs originates mainly from electrostatic interactions. At the same time, the calculated magnitude of the second order intramolecular correlation correction to the Coulomb energy showed that electron correlation reduces the contribution of the electrostatic term to the attractive interaction for the A-T and G-C base pairs. Polarization, charge transfer and dispersion interactions also make considerable contribution to the attraction energy of bases.     

On the nature of stability of the nucleotide base associates in water solution

Expression for the long-range intermolecular interaction energy obtained by the perturbation theory method in atomic dipole approximation are used for the study of the nature of base interaction in stacked dimers formed of two neighbouring DNA base pairs. Base wave functions are computed by the CNDO-CI method. The inplane interactions are shown to give the dominant contribution into the DNA stabilization energy in vacuum. The estimations performed for the solvent effect on intermolecular interaction energy allowed us to draw conclusions about the decisive role of hydrophobic interactions in a base stacking.     

Libraries of atomic multipole moments for precise modeling of electrostatic properties of amino acids

Summary Contemporary theoretical models used in describing electrostatic properties of amino acids in polypeptides rely usually on atomic point charges. Recently noted defects of such models in reproducing protein folding originate from the inadequate representation of the electrostatic term, in particular inability of atomic charges to account for local anisotropy of molecular charge distribution. Such defects could be corrected by multicenter multipole moments derived directly from any high quality quantum chemical wavefunctions. This is illustrated by comparison of monopole and multipole electrostatic interactions between some amino acids within glutathione S-transferase.High quality Point Charge Models (PCM) can be derived analytically from multipole moment databases. Preliminary results suggest that torsional potentials are controlled by electrostatic interactions of atomic multipoles.Examples illustrating various uses of multicenter multipole moment databases of protein building blocks in modeling various properties of amino acids and polypeptides have been described, including calculation of molecular electrostatic potentials, electric fields, interactions between amino acid residues, estimates of pK_a shifts and changes in catalytic activity induced by amino acid substitutions in mutated enzymes.     

Calculation and display of electrostatic potentials

A general methodology is developed for incorporating accurate electrostatic information from ab initio molecular orbital calculations into molecular mechanics calculations. Examples are given of the method applied to simple aromatic organic molecules. A program has been developed for displaying the results of the ab initio calculations on a Silicon Graphics workstation. The technique developed here provides an alternative method for including electrostatic interactions in molecular mechanics calculations and is compared with other methods for determining atomic charges.     

Intermolecular interactions between gold clusters and selected amino acids cysteine and glycine: a DFT study

The intermolecular interactions between Au_n (n = 3–4) clusters and selected amino acids cysteine and glycine have been investigated by means of density functional theory (DFT). Present calculations show that the complexes possessing Au-NH₂ anchoring bond are found to be energetically favored. The results of NBO and frontier molecular orbitals analysis indicate that for the complex with anchoring bonds, lone pair electrons of sulfur, oxygen, and nitrogen atoms are transferred to the antibonding orbitals of gold, while for the complex with the nonconventional hydrogen bonds (Au···H–O), the lone pair electrons of gold are transferred to the antibonding orbitals of O-H bonds during the interaction. Furthermore, the interaction energy calculations show that the complexes with Au-NH₂ anchoring bond have relatively high intermolecular interaction energy, which is consistent with previous computational studies.     

Towards an understanding of the arginine-aspartate interaction.

We have made a comparison of the geometries of intra- and intermolecular arginine-aspartate interactions by extracting orientation information from protein co-ordinate data. The results show a pronounced difference, with both types of interaction preferring to form twin N-H . . . O = C hydrogen bonds, but involving different nitrogen atoms. In intramolecular interactions, the aspartate favours a "side on" geometry, forming hydrogen bonds with N epsilon and N eta 2; in the intermolecular case, however, "end on" contacts involving N eta 1 and N eta 2 of the arginine are preferred. We have used Distributed Multipole Analysis of the methylguanidinium-acetate system to model the electrostatic component of the arginine-aspartate ion pair interaction in vacuo. We find, in agreement with the experimental arginine-aspartate distribution, that side on and end on doubly N-H . . . O = C hydrogen-bonded configurations are clearly the most favourable, with the side on being marginally lower in energy. Thus, despite the many competing side-chain interactions in proteins, many arginine-aspartate pairs adopt one of the minimum electrostatic energy conformations, or one close to a minimum. Within each of the two regions (side on and end on) we find only a small energy gap between the "symmetric" doubly hydrogen-bonded and slightly displaced "staggered" structures, again in agreement with the crystal structure data. Further calculations of the total ab initio interaction energy show that this follows the electrostatic term in its orientational variation, this phenomenon of "electrostatic domination" being well known in hydrogen-bonded systems. The end on arginine nitrogen atoms are observed to be more surface-exposed than N epsilon, as demonstrated by their greater accessibilities over a large sample of proteins. This helps explain the side on and end on preferences of intra- and intermolecular interactions, respectively. We also note the effect of short sequence intervals, particularly i in equilibrium with i + 2 relationships, in forcing many intramolecular contacts to be side on.     

Nonplanar DNA Base Pairs

Abstract

Three-dimensional structures of a representative set of more than 30 hydrogen-bonded nucleic acids base pairs have been studied by reliable ab initio quantum mechanical methods. We show that many hydrogen-bonded nucleic acid base pairs are intrinsically nonplanar, mainly due to the partial sp³ hybridization of nitrogen atoms of their amino groups and secondary electrostatic interactions. This finding extends the variability of intermolecular interactions of DNA bases in that i) flexibility of the base pairs is larger than has been assumed before, and ii) attractive proton-proton acceptor interactions oriented out of the base pair plane are allowed. For example, all four G…A mismatch base pairs are propeller twisted, and the energy preferences for the nonplanar structures range from less than 0.1 kcal/mol to 1.8 kcal/mol. We predict that nonplanarity of the amino group of guanine in the G(anti)…A(anti) pair of the ApG step of the d(CCAAGATTGG)₂ crystal structure is an important stabilizing factor that improves the energy of this structure by almost 3 kcal/mol. Currently used empirical potentials are not accurate enough to properly cover the interactions associated with amino-group and base-pair nonplanarity.     

Spatial optimization of electrostatic interactions between the ionized groups in globular proteins

A model approach is suggested to estimate the degree of spatial optimization of the electrostatic interactions in protein molecules. The method is tested on a set of 44 globular proteins, representative of the available crystallographic data. The theoretical model is based on macroscopic computation of the contribution of charge–charge interactions to the electrostatic term of the free energy for the native proteins and for a big number of virtual structures with randomly distributed on protein surface charge consetellations (generated by a Monte-Carlo technique). The statistical probability of occurrence of random structures with electrostatic energies lower than the energy of the native protein is suggested as a criterion for spatial optimization of the electrostatic interactions. The results support the hypothesis that the folding process optimizes the stabilizing effect of electrostatic interactions, but to very different degree for different proteins. A parallel analysis of ion pairs shows that the optimization of the electrostatic term in globular proteins has increasingly gone in the direction of rejecting the repulsive short contacts between charges of equal sign than of creating of more salt bridges (in comparison with the statistically expected number of shortrange ion pairs in the simulated random structures). It is observed that the decrease in the spatial optimization of the electrostatic interactions is usually compensated for by an appearance of disulfide bridges in the covalent structure of the examined proteins. © 1994 Wiley-Liss, Inc.     

Electrostatic interactions during electron transfer reactions between c-type cytochromes and flavodoxin

The interaction of three different c-type cytochromes with flavodoxin has been studied by computer graphics modelling and computational methods. Flavodoxin and each cytochrome can make similar hypothetical electron transfer complexes that are characterized by nearly coplanar arrangement of the prosthetic groups, close intermolecular contacts at the protein-protein interface, and complementary intermolecular salt linkages. Computation of the electrostatic free energy of each complex showed that all were electrostatically stable. However, both the magnitude and behavior of the electrostatic stabilization as a function of solution ionic strength differed for the three cytochrome c-flavodoxin complexes. Variation in the computed electrostatic stabilization appears to reflect differences in the surface distribution of all charged groups in the complex, rather than differences localized at the site of intermolecular contact. The computed electrostatic association constants for the complexes and the measured kinetic rates of electron transfer in solution show a remarkable similarity in their ionic strength dependence. This correlation suggests electrostatic interactions influence electron transfer rates between protein molecules at the intermolecular association step. Comparative calculations for the three cytochrome c-flavodoxin complexes show that these ionic strength effects also involve all charged groups in both redox partners.     

Improved electrostatic properties using combined Mulliken and hybridization-displaced charges for radicals

Effects of explicit consideration of charges displaced from atomic sites due to atomic orbital hybridization called hybridization-displaced charges (HDC) on dipole moments and surface molecular electrostatic potentials of certain radicals and their complexes with closed-shell molecules have been studied. HDC were computed for several radicals and their complexes at the B3LYP/6–31G** level of theory. At this level, HDC consist of three point charges associated with hydrogen atoms and seven point charges associated with heavy atoms belonging to the second row of the periodic table. HDC are so calculated that the contribution of each atom to the component of molecular dipole moment arising due to atomic orbital hybridization is preserved. It is found that dipole moments and electrostatic potentials of the systems studied here can be obtained with a significantly improved accuracy using a combination of Mulliken charges and HDC over that obtained by Mulliken charges only. Figure Surface MEP map of H₂O-HO· radical complex obtained using Mulliken charges combined with HDC     

Computer modelling of glycolipids at membrane surfaces.

Interactions of membrane anchored molecules such as glycolipids with a membrane surface are important in determining headgroup conformation. It is therefore essential to represent these membrane surface interactions in molecular modeling studies of glycolipids and other membrane bound molecules. We introduce here an energy term that represents the interaction of molecules with a membrane bilayer. This membrane interaction energy term has been added to the potential energy function of a molecular dynamics and mechanics program and has been parameterized using partition coefficients between an aqueous solution and a vesicular membrane for two model glycolipids.     

Excluded volume approximation to protein-solvent interaction. The solvent contact model.

Important properties of globular proteins, such as the stability of its folded state, depend sensitively on interactions with solvent molecules. Existing methods for estimating these interactions, such as the geometrical surface model, are either physically misleading or too time consuming to be applied routinely in energy calculations. As an alternative, we derive here a simple model for the interactions between protein atoms and solvent atoms in the first hydration layer, the solvent contact model, based on the conservation of the total number of atomic contacts, a consequence of the excluded-volume effect. The model has the conceptual advantage that protein-protein contacts and protein-solvent contacts are treated in the same language and the technical advantage that the solvent term becomes a particularly simple function of interatomic distances. The model allows rapid calculation of any physical property that depends only on the number and type of protein-solvent nearest-neighbor contacts. We propose use of the method in the calculation of protein solvation energies, conformational energy calculations, and molecular dynamics simulations.     

A molecular dynamics study of the C-terminal fragment of the L7/L12 ribosomal protein

The crystallographic dimer of the C-terminal fragment (CTF) of the L7/L12 ribosomal protein has been subjected to molecular dynamics (MD) simulations. A 90 picosecond (ps) trajectory for the protein dimer, 19 water molecules and two counter ions has been calculated at constant temperature. Effects of intermolecular interactions on the structure and dynamics have been studied. The exact crystallographic symmetry is lost and the atomic fluctuations differ from one monomer to the other. The average MD structure is more stable than the X-ray one, as judged by accessible surface area and energy calculations. Crystal (non-dimeric) interactions have been simulated in another 40 ps trajectory by using harmonic restraints to represent intermolecular hydrogen bonds. The conformational changes with respect ot the X-ray structure are then virtually suppressed.The unrestrained dimer trajectory has been scanned for cooperative motions involving secondary structure elements. The intrinsic collective motions of the monomer are transmitted via intermolecular contacts to the dimer structure.The existence of a stable dimeric form of CTF, resembling the crystallographic one, has been documented. At the cost of fairly small energy expenditure the dimer has considerable conformational flexibility. This flexibility may endow the dimer with some functional potential as an energy transducer.