Molecular mechanical perspective on halogen bonding

The nature and strength of halogen bonding in halo molecule-Lewis base complexes were studied in terms of molecular mechanics using our recently developed positive extra-point (PEP) approach, in which the σ-hole on the halogen atom is represented by an extra point of positive charge. The contributions of the σ-hole (i.e., positively charged extra point) and the halogen atom to the strength of this noncovalent interaction were clarified using the atomic parameter contribution to the molecular interaction (APCtMI) approach. The molecular mechanical results revealed that the halogen bond is electrostatic and van der Waals in nature, and its strength depends on three types of interaction: (1) the attractive electrostatic interaction between the σ-hole and the Lewis base, (2) the repulsive electrostatic interaction between the negative halogen atom and the Lewis base, and (3) the repulsive/attractive van der Waals interactions between the halogen atom and the Lewis base. The strength of the halogen bond increases with increasing σ-hole size (i.e., magnitude of the extra-point charge) and increasing halogen atom size. The van der Waals interaction's contribution to the halogen bond strength is most favorable in chloro complexes, whereas the electrostatic interaction is dominant in iodo complexes. The idea that the chloromethane molecule can form a halogen bond with a Lewis base was revisited in terms of quantum mechanics and molecular mechanics. Although chloromethane does produce a positive region along the C-Cl axis, basis set superposition error corrected second-order M?ller-Plesset calculations showed that chloromethane-Lewis base complexes are unstable, producing halogen-Lewis base contacts longer than the sum of the van der Waals radii of the halogen and O/N atoms. Molecular mechanics using the APCtMI approach showed that electrostatic interactions between chloromethane and a Lewis base are unfavorable owing to the high negative charge on the chlorine atom, which overcomes the corresponding favorable van der Waals interactions.     

Dielectric screening effect of electronic polarization and intramolecular hydrogen bonding

Recent site‐resolved hydrogen exchange measurements have uncovered significant discrepancies between simulations and experimental data during protein folding, including the excessive intramolecular hydrogen bonds in simulations. This finding indicates a possibility that intramolecular charge–charge interactions have not included sufficient dielectric screening effect of the electronic polarization. Scaling down peptide atomic charges according to the optical dielectric constant is tested in this study. As a result, the number of intramolecular hydrogen bonds is lower than using unscaled atomic charges while reaching the same levels of helical contents or β‐hairpin backbone hydrogen bonds, because van der Waals interactions contribute substantially to peptide folding in water. Reducing intramolecular charge–charge interactions and hydrogen bonding increases conformational search efficiency. In particular, it reduces the equilibrium helical content in simulations using AMBER force field and the energy barrier in folding simulations using CHARMM force field.     

Theoretical study of antagonists and inhibitors of mammalian adenosine deaminase. II. Isomeric aza-deazaanalogues of adenosine

Isomeric aza-deazaanalogues of adenosine and their N1-protonated forms (except for that of 8-aza-1-deazaadenosine) were studied by computer modeling to find a relationship between their molecular structures and the properties as substrates for the mammalian adenosine deaminase. The atomic charge distribution and maps of the electrostatic potential around their van der Waals molecular surface were calculated using the ab initio STO-3G method. The conformational studies were carried out by the MM+ method of molecular mechanics. The previously proposed mechanism of the substrate acceptance in the active site of mammalian adenosine deaminase was refined, and the potential substrate properties were predicted for two previously unstudied adenosine analogues, 5-aza-9-deazaadenosine and 8-aza-3-deazaadenosine.     

Theoretical Study of Antagonists and Inhibitors of Mammalian Adenosine Deaminase: I. Adenosine and Its Aza- and Deazaanalogues

Aza- and deazaanalogues of adenosine, including their 1-protonated forms (except for that of 1-deazaadenosine), were studied by computer computation to find a relationship between their molecular structures and substrate properties for the mammalian adenosine deaminase. The atomic charge distribution and maps of the electrostatic potential around their van der Waals molecular surface were calculated for these compounds using the ab initio STO-3G method. The conformational studies are carried out by the MM⁺ method of molecular mechanics. The mechanism that determines the substrate selectivity of mammalian adenosine deaminase is discussed.     

Theoretical study of antagonists and inhibitors of mammalian adenosine deaminase. I. Adenosine and its aza- and deaza-analogs

Aza- and deazaanalogues of adenosine, including their 1-protonated forms (except for that of 1-deazaadenosine), were studied by computer computation to find a relationship between their molecular structures and substrate properties for the mammalian adenosine deaminase. The atomic charge distribution and maps of the electrostatic potential around their van der Waals molecular surface were calculated for these compounds using the ab initio STO-3G method. The conformational studies were carried out by the MM+ method of molecular mechanics. The mechanism that determines the substrate selectivity of mammalian adenosine deaminase is discussed. The English version of the paper: Russian Journal of Bioorganic Chemistry, 2002, vol. 28, no. 4; see also http://www.maik.ru.     

Computing van der Waals energies in the context of the rotamer approximation

The rotamer approximation states that protein side-chain conformations can be described well using a finite set of rotational isomers. This approximation is often applied in the context of computational protein design and structure prediction to reduce the complexity of structural sampling. It is an effective way of reducing the structure space to the most relevant conformations. However, the appropriateness of rotamers for sampling structure space does not imply that a rotamer-based energy landscape preserves any of the properties of the true continuous energy landscape. Specifically, because the energy of a van der Waals interaction can be very sensitive to small changes in atomic separation, meaningful van der Waals energies are particularly difficult to calculate from rotamer-based structures. This presents a problem for computational protein design, where the total energy of a given structure is often represented as a sum of precalculated rigid rotamer self and pair contributions. A common way of addressing this issue is to modify the van der Waals function to reduce its sensitivity to atomic position, but excessive modification may result in a strongly nonphysical potential. Although many different van der Waals modifications have been used in protein design, little is known about which performs best, and why. In this paper, we study 10 ways of computing van der Waals energies under the rotamer approximation, representing four general classes, and compare their performance using a variety of metrics relevant to protein design and native-sequence repacking calculations. Scaling van der Waals radii by anywhere from 85 to 95% gives the best performance. Linearizing and capping the repulsive portion of the potential can give additional improvement, which comes primarily from getting rid of unrealistically large clash energies. On the other hand, continuously minimizing individual rotamer pairs prior to evaluating their interaction works acceptably in native-sequence repacking, but fails in protein design. Additionally, we show that the problem of predicting relevant van der Waals energies from rotamer-based structures is strongly nonpairwise decomposable and hence further modifications of the potential are unlikely to give significant improvement.     

Theoretical Study of Antagonists and Inhibitors of Mammalian Adenosine Deaminase: II. Isomeric Aza-deazaanalogues of Adenosine

Isomeric aza-deazaanalogues of adenosine and their N1-protonated forms (except for that of 8-aza-1-deazaadenosine) were studied by computer modeling to find a relationship between their molecular structures and the properties as substrates for the mammalian adenosine deaminase. The atomic charge distribution and maps of electrostatic potential around their van der Waals molecular surface were calculated using the ab initioSTO-3G method. The conformational studies were carried out by the MM⁺ method of molecular mechanics. The previously proposed mechanism of the substrate acceptance in the active site of mammalian adenosine deaminase was refined, and the potential substrate properties were predicted for two previously unstudied adenosine analogues, 5-aza-9-deazaadenosine and 8-aza-3-deazaadenosine.     

Van der Waals forces. Special characteristics in lipid-water systems and a general method of calculation based on the Lifshitz theory

A practical method for examining and calculating van der Waals forces is derived from Lifshitz'' theory. Rather than treat the total van der Waals energy as a sum of pairwise interactions between atoms, the Lifshitz theory treats component materials as continua in which there are electromagnetic fluctuations at all frequencies over the entire body. It is necessary in principle to use total macroscopic dielectric data from component substances to analyze the permitted fluctuations; in practice it is possible to use only partial information to perform satisfactory calculations. The biologically interesting case of lipid-water systems is considered in detail for illustration. The method gives good agreement with measured van der Waals energy of interaction across a lipid film. It appears that fluctuations at infrared frequencies and microwave frequencies are very important although these are usually ignored in preference to UV contributions. “Retardation effects” are such as to damp out high frequency fluctuation contributions; if interaction specificity is due to UV spectra, this will be revealed only at interactions across <200 angstrom (A). Dependence of van der Waals forces on material electric properties is discussed in terms of illustrative numerical calculations.     

Stereochemical complementarity of progesterone and cavities between base pairs in partially unwound double stranded DNA using computer modeling and energy calculations to determine degree of fit

Computer modeling was applied for the first time to investigate previously reported complementarity of progesterone and cavities formed between base pairs in partially unwound double stranded DNA. Computer graphics enabled a more objective assessment of complementarity; energy calculations provided a rigorous method to evaluate degree of fit. Graphics confirmed that the complementarity was virtually "lock and key", i.e. close contacts were formed between van der Waals surfaces in the progesterone/DNA complexes and hydrogen bonds were formed between the two carbonyl groups on opposite ends of the steroid and phosphate groups on adjacent strands of DNA. Molecular mechanics calculations revealed that insertion of the steroid resulted in a relatively stable complex i.e. both van der Waals and electrostatic energies were lowered due to favorable steric interactions and stereospecific hydrogen bonds, respectively. Three published X-ray crystal structures of progesterone exhibited similar complementarity. Ent-progesterone which does not occur naturally possessed very poor complementarity. These findings confirm that the structure of progesterone is directly reflected in the stereochemistry of DNA. While no mechanistic explanation for these results is proffered, we hypothesize that such complementarity must have played a decisive role in the evolution of steroid hormone structure and function.     

Binding to δ and μ opioid receptors by deltorphin I/II analogues modified at the Phe and Asp/Glu side chains: a report of 32 new analogues and a QSAR study

The synthesis and binding affinities of 32 X³Gly⁴ dual-substitution analogues of the natural opioid heptapeptides deltorphin I and II are reported. A multiple regression QSAR analysis was performed using those results along with literature data for the X³Asp⁴ and Phe³X⁴ side chain analogues. Fitting to a three-term potential well model with hydrophobic and van der Waals attraction terms and a steric repulsion term indicates that the δ and μ receptor sites for binding the residue three side chain are similar, and that the binding interaction is primarily van der Waals and secondarily hydrophobic. Further analysis indicates that both sites are more constrained with respect to side chain length than width or thickness, and the μ site appears to be somewhat larger. A binding model consistent with these findings pictures the native third residues Phe ring laying on a step notched out of the receptor surface, pointing toward the back (riser) of the step, and sandwiched between the receptor and ligand. However, the binding sites for the residue four side chains are quite different on δ and μ receptors. Binding to the δ site appears to involve both electrostatic attraction (probably to a partial positive charge) and van der Waals attraction, but not necessarily hydrogen bonding, and more constraint with respect to side chain length than width or thickness. In contrast, there is no evidence for any kind of binding attraction between the side chain of residue four and the μ site, which acts more as steric repulsion site, as though the space that is a pocket on the δ receptor is filled in on the μ receptor. A regression model based only on steric repulsion by van der Waals bulk and/or the effective bulk of a hydration layer accounts for over 80% of the residue four related variation in μ affinity.

Abstract

Thirty-two new X³Gly⁴ analogues of deltrophin I/II opioid peptides are described. A QSAR study of the X³Gly⁴, X³Asp⁴, and Phe³X⁴ analogue series using a potential well model reveals the roles of hydrophobic, van der Waals, electrostatic, hydrogen bonding and steric interactions in δ and μ receptor binding of X³ and X⁴ side chains.     

Molecular similarity analysis between insect juvenile hormone and N, N-diethyl-m-toluamide (DEET) analogs may aid design of novel insect repellents

Molecular similarity analysis of stereoelectronic properties between natural insect juvenile hormone (JH), -a synthetic insect juvenile hormone mimic (JH-mimic, undecen-2-yl carbamate), and N, N-diethyl-m-toluamide (DEET) and its analogs reveals similarities that may aid the design of more efficacious insect repellents and give a better insight into the mechanism of repellent action. The study involves quantum chemical calculations using the AM1 semi-empirical computational method enabling a conformational search for the lowest and most abundant energy conformers of JH, JH-mimic, and 15 DEET compounds, followed by complete geometry optimization of the conformers. Similarity analyses of stereoelectronic properties such as structural parameters, atomic charges, dipole moments, molecular electrostatic potentials, and highest occupied molecular orbital (HOMO) and lowest unoccupied molecular orbital (LUMO) energies were performed on JH, JH-mimic and the DEET compounds. The similarity of stereoelectronic attributes of the amide/ester moiety, the negative electrostatic potential regions beyond the van der Waals surface, and the large distribution of hydrophobic regions in the compounds appear to be the three important factors leading to a similar interaction with the JH receptor. The similarity of electrostatic profiles beyond the van der Waals surface is likely to play a crucial role in molecular recognition interaction with the JH receptor from a distance. This also suggests electrostatic bioisosterism of the amide group of the DEET compounds and JH-mimic and, thus, a model for molecular recognition at the JH receptor. The insect repellent property of the DEET analogs may thus be attributed to a conflict of complementarity for the JH receptor binding sites.     

Solvation thermodynamics of biopolymers. I. Separation of the volume and surface interactions with estimates for proteins

The present paper is a systematic first approach to the problem of solvation thermodynamics of biomolecules. Most previous approaches have been only crude estimates of solvent contributions, and have simply assessed solvation free energy as proportional to surface areas. Here we estimate the various contributions and divide them into (a) hard-core interactions dependent upon the entire volume of solute and (b) the remainder of interactions manifested through surfaces, such as van der Waals, charge-charge, or hydrogen bonds. We have estimated the work to create a cavity with scaled-particle theory (SPT), the van der Waals interactions on the surface, and hydrogen bonds between the surface and the solvent. The conclusion here is that this latter term is the largest component of the solvation free energy of proteins. From estimates on nine diverse proteins, it is clear that the larger the protein, the more dominant is the hydrogen-bond term. In the next paper, we indicate that correlations between hydrogen-bonding groups on the surfaces could increase the magnitude of the hydrogen-bond contribution.     

SCORE: A New Empirical Method for Estimating the Binding Affinity of a Protein-Ligand Complex

A new method is presented to estimate the binding affinity of a protein-ligand complex with known three-dimensional structure. The method, SCORE, uses an empirical scoring function to describe the binding free energy, which includes terms to account for van der Waals contact, metal-ligand bonding, hydrogen bonding, desolvation effect, and deformation penalty upon the binding process. The coefficients of each term are obtained by multivariate regressional analysis of a diverse training set of 170 protein-ligand complexes. The final scoring function reproduces the binding free energies of the whole training set with a cross-validated deviation of 6.3 kJ/mol. The predictive ability of the function is further tested by a set of 11 endothiapepsin complexes and the internal consistency of the function is demonstrated in a stepwise procedure named Evolutionary Test. A major innovation of this method is the introduction of an atomic binding score which allows the researcher to inspect and optimize the lead compound rationally in a structure-based drug design scheme.     

Morphology of modified regenerated model cellulose II surfaces studied by atomic force microscopy: effect of carboxymethylation and heat treatment

Model cellulose II surfaces with different surface charge have been prepared from carboxymethylated wood pulp. AFM tapping-mode imaging in air showed that the introduction of charged groups into the film does not appreciably change the surface morphology. However, after a mild heat treatment (heating at 105 degrees C for 6 h), an irreversible surface structure change, from near spherical-type aggregates to a fibrillar structure, was observed. This might be attributed to the formation of strong hydrogen bonds in the crystalline region of the films while the amorphous regions shrank upon drying. The suitability of these charged cellulose films for surface forces studies was also investigated. At pH below the pK(a) of the carboxyl groups present in the film, the interaction force could be fit by a van der Waals force interaction. At higher pH, the interaction was of a purely electrostatic nature with no van der Waals component observable due to the swelling of the surfaces.     

Adhesion of the positively charged bacterium Stenotrophomonas (Xanthomonas) maltophilia 70401 to glass and Teflon.

Medical implants are often colonized by bacteria which may cause severe infections. The initial step in the colonization, the adhesion of bacteria to the artificial solid surface, is governed mainly by long-range van der Waals and electrostatic interactions between the solid surface and the bacterial cell. While van der Waals forces are generally attractive, the usually negative charge of bacteria and solid surfaces leads to electrostatic repulsion. We report here on the adhesion of a clinical isolate, Stenotrophomonas maltophilia 70401, which is, at physiological pH, positively charged. S. maltophilia has an electrophoretic mobility of +0.3 x 10(-8) m2 V-1 s-1 at pH 7 and an overall surface isoelectric point at pH 11. The positive charge probably originates from proteins located in the outer membrane. For this bacterium, both long-range forces involved in adhesion are attractive. Consequently, adhesion of S. maltophilia to negatively charged surfaces such as glass and Teflon is much favored compared with the negatively charged bacterium Pseudomonas putida mt2. While adhesion of negatively charged bacteria is impeded in media of low ionic strength because of a thick negatively charged diffuse layer, adhesion of S. maltophilia was particularly favored in dilute medium. The adhesion efficiencies of S. maltophilia at various ionic strengths could be explained in terms of calculated long-range interaction energies between S. maltophilia and glass or Teflon.     

Reduced point charge models of proteins: assessment based on molecular dynamics simulations

A reduced point charge distribution is used to model Ubiquitin and two complexes, Vps27 UIM-1–Ubiquitin and Barnase–Barstar. It is designed from local extrema in charge density distributions obtained from the Poisson equation applied to smoothed molecular electrostatic potentials. A variant distribution is built by locating point charges on atoms. Various charge fitting conditions are selected, i.e. from either electrostatic Amber99 (Assisted Model Building with Energy Refinement) Coulomb potential or forces, considering reference grid points located within various distances from the protein atoms, with or without separate treatment of main and side chain charges. The program GROMACS (Groningen Machine for Chemical Simulations) is used to generate Amber99SB molecular dynamics (MD) trajectories of the solvated proteins modelled using the various reduced point charge models (RPCMs) so obtained. Point charges that are not located on atoms are considered as virtual sites. Some RPCMs lead to stable MD trajectories. They, however, involve a partial loss in the protein secondary structure and lead to a less-structured solute solvation shell. The model built by fitting charges on Coulomb forces calculated at grid points ranging between 1.4 and 2.0 times the van der Waals radius of the atoms, with a separate treatment of main chain and side chain charges, appears to best approximate all-atom MD trajectories.     

Temperature-dependent van der Waals forces

Biological systems can experience a strong van der Waals interaction involving electromagnetic fluctuations at the low frequency limit. In lipid-water mixtures the free energy of this interaction is proportional to temperature, primarily involves an entropy change, and has qualitative features of a “hydrophobic bond.” Protein-protein attraction in dilute solution is due as much to low frequency proton fluctuation (Kirkwood-Shumaker forces) and permanent dipole forces as to high frequency (infrared and UV) van der Waals intreactions. These conclusions are described in terms of numerical calculations via the Lifshitz theory of van der Waals forces.     

Monte Carlo refinement of rigid-body protein docking structures with backbone displacement and side-chain optimization

Structures of hitherto unknown protein complexes can be predicted by docking the solved protein monomers. Here, we present a method to refine initial docking estimates of protein complex structures by a Monte Carlo approach including rigid-body moves and side-chain optimization. The energy function used is comprised of van der Waals, Coulomb, and atomic contact energy terms. During the simulation, we gradually shift from a novel smoothed van der Waals potential, which prevents trapping in local energy minima, to the standard Lennard-Jones potential. Following the simulation, the conformations are clustered to obtain the final predictions. Using only the first 100 decoys generated by a fast Fourier transform (FFT)-based rigid-body docking method, our refinement procedure is able to generate near-native structures (interface RMSD <2.5 A) as first model in 14 of 59 cases in a benchmark set. In most cases, clear binding funnels around the native structure can be observed. The results show the potential of Monte Carlo refinement methods and emphasize their applicability for protein-protein docking.     

Computational protocol for predicting the binding affinities of zinc containing metalloprotein-ligand complexes

Zinc is one of the most important metal ions found in proteins performing specific functions associated with life processes. Coordination geometry of the zinc ion in the active site of the metalloprotein-ligand complexes poses a challenge in determining ligand binding affinities accurately in structure-based drug design. We report here an all atom force field based computational protocol for estimating rapidly the binding affinities of zinc containing metalloprotein-ligand complexes, considering electrostatics, van der Waals, hydrophobicity, and loss in conformational entropy of protein side chains upon ligand binding along with a nonbonded approach to model the interactions of the zinc ion with all the other atoms of the complex. We examined the sensitivity of the binding affinity predictions to the choice of Lennard-Jones parameters, partial atomic charges, and dielectric treatments adopted for system preparation and scoring. The highest correlation obtained was R2 = 0.77 (r = 0.88) for the predicted binding affinity against the experiment on a heterogenous dataset of 90 zinc containing metalloprotein-ligand complexes consisting of five unique protein targets. Model validation and parameter analysis studies underscore the robustness and predictive ability of the scoring function. The high correlation obtained suggests the potential applicability of the methodology in designing novel ligands for zinc-metalloproteins. The scoring function has been web enabled for free access at www.scfbio-iitd.res.in/software/drugdesign/bapplz.jsp as BAPPL-Z server (Binding Affinity Prediction of Protein-Ligand complexes containing Zinc metal ions).     

Long range intermolecular forces between macroscopic bodies: macroscopic and microscopic approaches.

Van der Waals energies of interaction are calculated by two methods, the macroscopic method of Lifshitz and the microscopic method of London-Casimir and Polder-Hamaker for the case of two semi-infinite slabs separated by a thin film. When retardation effects may be neglected, the London-Hamaker approach yields values of dispersion interactions which almost coincide with those of the Lifshitz approach, the magnitude of the former values being larger by approximately 10–25%, which is attributed to the effect of the molecular environment in condensed media. At 50–100 Å film thicknesses where retardation effects are small, dispersion terms are generally the major part of van der Waals forces in the Lifshitz formulation. Hence, for 50–100 Å film thicknesses the Hamaker approach, which only includes dispersion interactions is generally adequate. By accounting for retardation effects, which significantly reduce the magnitude of dispersion interactions at several hundred Å, there is a reasonable agreement between the values obtained by the macroscopic and microscopic approaches. When polar substances are present and for film thicknesses of several hundred Å, where dispersion interactions are significantly reduced, the major contribution to van der Waals forces may arise from orientation and induction terms. For such cases the Hamaker approach may lead to critical underestimates of the calculated magnitude of van der Waals forces. An ad hoc way to overcome this difficulty which is applicable to any geometry is proposed. This study presents a simple procedure for the determination of free energies of interaction between macroscopic bodies of various shapes. The procedure, which is applicable when the molecules of bodies and surrounding medium are isotropic, yields results which closely approximate those obtained with the Lifshitz theory.