Calculation of binding affinities of HIV-1 RT and β-secretase inhibitors using the linear interaction energy method with explicit and continuum solvation approaches

The linear interaction energy (LIE) approach has been applied to estimate the binding free energies of representative sets of HIV-1 RT and β-Secretase inhibitors, using both molecular dynamics (MD) and tethered energy minimization sampling protocols with the OPLS-AA potential, using a range of solvation methodologies. Generalized Born (GB), ‘shell’ and periodic boundary condition (PBC) solvation were used, the latter with reaction field (RF) electrostatics. Poisson-Boltzmann (PB) and GB continuum electrostatics schemes were applied to the simulation trajectories for each solvation type to estimate the electrostatic ligand-water interaction energy in both the free and bound states. Reasonable agreement of the LIE predictions was obtained with respect to experimental binding free energy estimates for both systems: for instance, ‘PB’ fits on MD trajectories carried out with PBC solvation and RF electrostatics led to models with standard errors of 1.11 and 1.03 kcal mol⁻¹ and coefficients of determination, r ² of 0.76 and 0.75 for the HIV-1 RT and β-Secretase sets. However, it was also found that results from MD sampling using PBC solvation provided only slightly better fits than from simulations using shell or Born solvation or tethered energy minimization sampling. Figure Evolution of the running averages for compound H11 (binding to HIV-1RT) of the bound state ligand-water and ligand-protein interaction energies. The ligand-water electrostatic terms are twice the corresponding GB and PB electrostatic solvation free energies. The ligand-receptor van der Waals and Coulombic interaction energies are also shown, in addition to the ligand-water van der Waals interaction term. The terms were calculated (without application of a cut-off) from a trajectory sampled under PBC solvation with reaction field electrostatics Electronic supplementary material The online version of this article (doi:) contains supplementary material, which is available to authorized users.     

Molecular electrostatic potentials in aromatic substituted 4-hydroxyquino-2-lones: Glycine/NMDA receptor antagonists

Hydroxyquinolone derivatives have proven to be useful for inhibition at the glycine binding site of N-methyl-D-aspartate (NMDA) receptor. In this work the electronic structure, molecular electrostatic potential (MESP) and vibrational characteristics of a set of C₃ substituted 4-hydroxyquino-2-lone (HQ) derivatives, which act as Glycine/NMDA receptor antagonists, have been investigated using the density functional calculations. In the optimized structures a substituent at the C₃ site of HQ tends to adopt a helical structure. MESP investigations reveal that the ligands showing better inhibition activity should possess electron-rich regions extending over the substituent and carbonyl group of HQ. A correlation of inhibitory activity to the molecular electrostatic potential topography at the carbonyl oxygen as well as to the molecular electron density topography turns out to be a significant output of the investigation. Figure Quantam chemical approach has been employed to understand the reactivity of a set of hydroxyquinolone derivatives known for their inhibition activity towards Glycine/NMDA receptor. Molecular electrostatic potential topography has been used as a tool to understand the reactivity pattern     

Study of a ligand complexed with Cdk2/Cdk4 by computer simulation

Cyclin-dependent kinases (Cdks) play important roles in the regulation of the cell cycle. Their inhibitors have entered clinical trials to treat cancer. Very recently, Davis et al. (Nat Struct Biol 9:745–749, 2002) have found a ligand NU6102, which has a high affinity with cyclin-dependent kinase 2 (K _i =6 nM) but a low affinity with cyclin-dependent kinase 4 (K _i =1,600 nM). To understand the selectivity, we use homology modeling, molecular docking, molecular dynamics and free-energy calculations to analyze the interactions. A rational 3D model of the Cdk4–NU6102 complex is built. Asp86 is a key residue that recognizes NU6102 more effectively with Cdk2 rather than Cdk4. Good binding free energies are obtained. Energetic analysis reveals that van der Waals interaction and nonpolar contributions to solvent are favorable in the formation of complexes and the sulfonamide group of the ligand plays a crucial role for binding selectivity between Cdk2 and Cdk4. Figure Two-dimensional representative for the interacting model of NU6102 complexed with the Cdk4 from a predicted structure by LIGPLOT.      

Development of realistic models for Double Metal Cyanide catalyst active sites

Realistic molecular models of one and two-centre catalytic active sites originating from the cleavage of a precursor material known to give rise to an active double metal cyanide catalyst are described. Via periodic density functional calculations the structure of the proposed catalytic sites are shown to be dependent on electrostatic and structural relaxation processes occurring at the surfaces of the precursor material. It is shown how these effects may be adequately captured by small molecular models of the active sites. The general methodology proposed should provide a computationally efficient basis for detailed future studies into catalytic reactions over double metal cyanide materials. Figure Reconstructed DMC [100]-surface: electrostatic potential mapped on charge density isosurface This work has been originally presented on the Modelling and Design of Molecular Materials conference in Wrocław, Poland.     

Structural insights into the effect of isonucleosides on B-DNA duplexes using molecular-dynamics simulations

Some structural insights into the conformations of the isonucleosides containing duplexes have been provided. Unrestrained molecular-dynamics simulations on 18-mer duplexes with isonucleosides incorporated at the 3'-end or in the center of one strand have been carried out with explicit solvent under periodic boundary conditions using the AMBER force field and the particle mesh Ewald method. The Watson–Crick hydrogen-bonding patterns of the duplexes studied remained intact throughout the simulation. For the modified duplexes, the changes observed in the inter-base pair parameters and backbone torsional angles were primarily localized at the isonucleoside-inserted area. All five structures studied remained in the B-form family. The decreased stacking abilities indicated by the large changes in inter-base pair parameters and the large changes in backbones made the modified duplexes show a minor thermal destabilization in comparison with native DNA. The MM_PBSA method for estimating binding free energies on two complementary strands was used. The results showed that the binding free energies of isonucleoside-incorporated DNA duplexes were lower than the native DNA duplex, which is in good agreement with experimental observations.      

Ion pairs and their role in modulating stability of cold- and warm-active uracil DNA glycosylase

MD simulations and continuum electrostatics calculations have been used to study the observed differences in thermostability of cold- and warm-active uracil DNA glycosylase (UDG). The present study focuses on the role of ion pairs and how they affect the thermal stability of the two enzymes. Analysis of the MD generated structural ensembles show that cod UDG (cUDG) and human UDG (hUDG) have 11 and 12 ion pairs which are present in at least 30% of the conformations. The electrostatic contribution of the ion pairs, computed using continuum electrostatics, is slightly more favorable in cUDG at 298 K. This is primarily attributed to more optimized interactions between the ion pairs and nearby dipoles/charges in cUDG. More global salt bridges are found in hUDG and are more stabilizing when compared to cUDG, possibly playing a role in maintaining overall stability and reducing conformational entropy. Both enzymes contain one three-member ionic network, but the one found in hUDG is far more stabilizing. Our results also suggest that care should be taken when performing statistical analysis of crystal structures with respect to ion pairs, and that crystallization conditions must be carefully examined when performing such analysis.     

Probing the nature of hydrogen bonds in DNA base pairs

Energy decomposition analyses based on the block-localized wave-function (BLW-ED) method are conducted to explore the nature of the hydrogen bonds in DNA base pairs in terms of deformation, Heitler–London, polarization, electron-transfer and dispersion-energy terms, where the Heitler–London energy term is composed of electrostatic and Pauli-exchange interactions. A modest electron-transfer effect is found in the Watson–Crick adenine–thymine (AT), guanine–cytosine (GC) and Hoogsteen adenine-thymine (H-AT) pairs, confirming the weak covalence in the hydrogen bonds. The electrostatic attraction and polarization effects account for most of the binding energies, particularly in the GC pair. Both theoretical and experimental data show that the GC pair has a binding energy (−25.4 kcal mol⁻¹ at the MP2/6-31G** level) twice that of the AT (−12.4 kcal mol⁻¹) and H-AT (−12.8 kcal mol⁻¹) pairs, compared with three conventional N-H···O(N) hydrogen bonds in the GC pair and two in the AT or H-AT pair. Although the remarkably strong binding between the guanine and cytosine bases benefits from the opposite orientations of the dipole moments in these two bases assisted by the π-electron delocalization from the amine groups to the carbonyl groups, model calculations demonstrate that π-resonance has very limited influence on the covalence of the hydrogen bonds. Thus, the often adopted terminology “resonance-assisted hydrogen bonding (RHAB)” may be replaced with “resonance-assisted binding” which highlights the electrostatic rather than electron-transfer nature of the enhanced stabilization, as hydrogen bonds are usually regarded as weak covalent bonds. Figure Electron density difference (EDD) maps for the GC pair: a shows the polarization effect (isodensity 1.2×10⁻³ a.u.); b shows the charge transfer effect (isodensity 2×10⁻⁴ a.u.) Dedicated to Professor Paul von Ragué Schleyer on the occasion of his 75th birthday     

Pattern recognition based on color-coded quantum mechanical surfaces for molecular alignment

A pattern recognition algorithm for the alignment of drug-like molecules has been implemented. The method is based on the calculation of quantum mechanical derived local properties defined on a molecular surface. This approach has been shown to be very useful in attempting to derive generalized, non-atom based representations of molecular structure. The visualization of these surfaces is described together with details of the methodology developed for their use in molecular overlay and similarity calculations. In addition, this paper also introduces an additional local property, the local curvature (C _L), which can be used together with the quantum mechanical properties to describe the local shape. The method is exemplified using some problems representing common tasks encountered in molecular similarity. Figure Molecular surfaces for Lorazepam (left) and Diazepam (right)     

A theoretical investigation of cytotoxic activity of celastroid triterpenoids

Quantum chemical calculations at the B3LYP/6-31G* level of theory have been carried out on 20 celastroid triterpenoids to obtain a set of molecular electronic properties and to correlate these with cytotoxic activities. The cytotoxic activities of these compounds can be roughly correlated with electronic effects related to nucleophilic addition to C(6) of the compounds: The energies of the frontier molecular orbitals (E _HOMO and E _LUMO), the HOMO-LUMO energy gap, the dipole moment, the charge on C(6), and the electrophilicity on C(6). Figure LUMO of Pristimerin.     

First principles calculations on the influence of water-filled cavities on the electronic structure of Prussian Blue

Prussian Blue is a paradigmatic mixed valence material and a parent compound to a broad family of electronically, optically, and magnetically active materials. Its exact composition varies greatly depending on the preparation route, leading to large variations in its electronic properties. The influence of water molecules on the structural and electronic properties of Prussian Blue were studied using state-of-the-art first principles calculations. Water-filled cavities were found to have a profound influence on the band gap and density of states of this material while simultaneously leaving many of its properties largely unchanged. The resulting model of an almost independent superimposition of dehydrated material and hydrated sites is briefly discussed. Unit cell of “insoluble” Prussian Blue used in calculations     

Optimisation of the surface electrostatics as a strategy for cold adaptation of uracil-DNA N-glycosylase (UNG) from Atlantic cod (Gadus morhua)

Cold-adapted enzymes are characterised by an increased catalytic efficiency and reduced temperature stability compared to their mesophilic counterparts. Lately, it has been suggested that an optimisation of the electrostatic surface potential is a strategy for cold adaptation for some enzymes. A visualisation of the electrostatic surface potential of cold-adapted uracil-DNA N-glycosylase (cUNG) from Atlantic cod indicates a more positively charged surface near the active site compared to human UNG (hUNG). In order to investigate the importance of the altered surface potential for the cold-adapted features of cod UNG, six mutants have been characterised and compared to cUNG and hUNG. The cUNG quadruple mutant (V171E, K185V, H250Q and H275Y) and four corresponding single mutants all comprise substitutions of residues present in the human enzyme. A human UNG mutant, E171V, comprises the equivalent residue found in cod UNG. In addition, crystal structures of the single mutants V171E and E171V have been determined. Results from the study show that a more negative electrostatic surface potential reduces the activity and increases the stability of cod UNG, and suggest an optimisation of the surface potential as a strategy for cold-adaptation of this enzyme. Val171 in cod UNG is especially important in this respect.     

Identification,cloning, and expression of uracil-DNA glycosylase from Atlantic cod (<Emphasis Type="Italic">Gadus morhua</Emphasis>): characterization and homology modeling of the cold-active catalytic domain

Two distinct forms of the highly conserved uracil-DNA glycosylase (UNG) have been isolated from Atlantic cod (Gadus morhua) liver cDNA by rapid amplification of cDNA ends (RACE). From the cDNA sequences, both forms were deduced to encode an open reading frame of 301 amino acids, with an identical 267-amino-acid C-terminal region and different N-terminal regions of 34 amino acids. By comparison with the human UNG sequences, the two forms were identified as possible mitochondrial (cUNG1) and nuclear (cUNG2) forms. Several constructs of recombinant cUNG (rcUNG) were expressed in Escherichia coli in order to optimize the yield. The recombinant enzyme was purified to apparent homogeneity as determined by sodium dodecyl sulfate-polyacrylamide gel electrophoresis. Activity and stability experiments showed that rcUNG was similar to cUNG previously purified from Atlantic cod liver, and was more pH- and temperature labile than a recombinant human UNG (rhUNG). Under optimal assay conditions for both rcUNG and rhUNG, the turnover number (k(cat)) was three times higher for rcUNG compared with rhUNG, with an identical K(M), resulting in a threefold higher catalytic efficiency (k(cat)/K(M)) for rcUNG. These activity and stability experiments reveal cold-adapted features in rcUNG. Homology models of the catalytic domains of Atlantic cod (cUNG) and mouse uracil-DNA glycosylase (mUNG) were built using the human UNG (hUNG) crystal structure as a template. The unique amino acid substitutions observed in cod UNG were mainly located in the N- and C-terminal parts of the sequence. The analysis indicated a more stable N-terminal, a more flexible C-terminal, and a less stabilized core in cUNG as compared with the mammalian UNGs. Substitution of several amino acids in or near the DNA-binding site in cUNG could give rise to a more positively charged surface and a higher electrostatic potential near the active site compared with the mammalian UNGs. The higher potential may increase the electrostatic interactions between the enzyme and DNA, and may explain the increased substrate affinity and, in combination with the higher flexibility, the higher catalytic efficiency observed for rcUNG.     

An experimental and theoretical study of the enantioselective deprotonation of cyclohexene oxide with isopinocampheyl-based chiral lithium amides

The mechanism of the enantioselective deprotonation of cyclohexene oxide with isopinocampheyl-based chiral lithium amide was studied by quantum chemical calculations. The transition states of eight molecules were fully optimized at the ab initio HF/3-21G and density functional B3LYP/3-21G levels with Gaussian 98. The activation energies were calculated at the B3LYP/6-31+G(3df,2p)//B3LYP/3-21G level. We found the theoretical evaluation to be consistent with the experimental data. At the best case, an enantiomeric excess of up to 95% for (R)-2-scyclohexen-1-ol was achieved with (−)-N, N-diisopinocampheyl lithium amide. Enantioselective deprotonation of cyclohexene oxide Electronic Supplementary Material Supplementary material is available for this article at Dedicated to Professor Dr. Paul von Ragué Schleyer on the occasion of his 75th birthday.     

The effect of salt concentration on DNA conformation transition: a molecular-dynamics study

We performed three 3-ns molecular dynamics simulations of d(CGCGAATTCGCG)₂ using the AMBER 8 package to determine the effect of salt concentration on DNA conformational transitions. All the simulations were started with A-DNA, with different salt concentrations, and converged with B-DNA with similar conformational parameters. However, the dynamic processes of the three MD simulations were very different. We found that the conformation transition was slow in the solution with higher salt concentration. To determine the cause of this retardation, we performed three additional 1.5-ns simulations starting with B-DNA and with the salt concentrations corresponding to the simulations mentioned above. However, astonishingly, there was no delayed conformation evolution found in any of the three simulations. Thus, our simulation conclusion is that higher salt concentrations slows the A → B conformation transition, but have no effect on the final stable structure. Figure A-DNA and B-DNA. (a) is the canonical A-DNA, and (b) is the canonical B-DNA. Looking from the central major groove     

Docking studies on kinesin spindle protein inhibitors: an important cooperative ‘minor binding pocket’ which increases the binding affinity significantly

Fifteen KSP inhibitors were docked into the receptor and the binding mode was analyzed for the first time. It was considered that in addition to the main binding pocket all the inhibitors merged in, there exists a cooperative minor binding pocket, which could be explored for significantly increased binding affinity. In addition, a good linear relationship between the biological activities and the lowest binding free energies has also been found. This may help in predicting the binding affinity of newly designed KSP inhibitors. Figure Two binding pockets considered after the analysis. Seven docked ligands (compound 1–7) were overlapped at the binding site. All inhibitors tested interacted with the main pocket, while CK0106023, interacted also with the cooperative minor pocket mainly surrounded by Arg221 and Ala218. Coloring of the binding site surface are different ends of each amino acid residue: blue represents amino group while red means carboxyl     

The electrostatic embedding contribution to DFT calculations of ligand-amino acid residues interaction

In this work, we demonstrate that the inclusion of long-range interactions has a significant impact on the estimation of ligand–protein binding energies. Within the scope of the electrostatically embedded adaptation of the molecular fragmentation with conjugated caps (EE-AMFCC) scheme, we unveil the role played by long-range contributions in distinct levels of quantum mechanical calculations. As a prototypical system, we consider ibuprofen coupled to the human serum albumin. In particular, we show that some relevant ligand–residue interaction energies can only be accurately captured in density functional theory (DFT) approaches when the electrostatic background is properly represented by an explicit point charge distribution.

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Graphical Abstract (left) The binding site FA3/FA4 of HSA containing the attached IBU. (right) Absolute value of difference between the biding energies calculated including the electrostatic embedding and the energies calculated without the electrostatic embedding using the HF, B3LYP, CAM-B3LYP, and MP2 methodologies

     

CoMFA study of distamycin analogs binding to the minor-groove of DNA: a unified model for broad-spectrum activity

A 3D-QSAR analysis has been carried out by comparative molecular field analysis (CoMFA) on a series of distamycin analogs that bind to the DNA of drug-resistant bacterial strains MRSA, PRSP and VSEF. The structures of the molecules were derived from the X-ray structure of distamycin bound to DNA and were aligned using the Database alignment method in Sybyl. Statistically significant CoMFA models for each activity were generated. The CoMFA contours throw light on the structure activity relationship (SAR) and help to identify novel features that can be incorporated into the distamycin framework to improve the activity. Common contours have been gleaned from the three models to construct a unified model that explains the steric and electrostatic requirements for antimicrobial activity against the three resistant strains. Figure A unified CoMFA model for broad-spectrum DNA minor-groove binders     

Interactions in pseudorotoxanes based on crown ether-secondary ammonium motifs. A theoretical study

A theoretical analysis of the nature of the interactions in dibenzo[24]crown-8 (DB24C8)-n-dibutylammonium (DBM)—pseudorotaxane complex at the MP2 and DFT levels shows that the main contribution to the binding energy is the electrostatic interaction with moderate (20–25%) correlation stabilization. The total binding energy in the DB24C8-DBM complex represents a sum of the binding energies of two NH–O and one CH–O hydrogen bonds and the latter constitutes about 25% of the total interaction energy, giving the total binding energy of −41.2 kcal mol⁻¹ at the BHandHLYP/6-311++G** level. Deprotonation of the DB24C8-DBM complex reduces the binding energy by some 50 kcal mol⁻¹, giving metastable complexes DB24C8-DBA-1 or DB24C8-DBA-2, which will dissociate to give free crown ether and n-dibutylamine because of the strong exchange repulsion that prevails in neutral complexes. Figure Formation of DB24C8-DBM pseudorotoxane complex     

Alpha particle chemistry. On the formation of stable complexes between He2+ and other simple species: implications for atmospheric and interstellar chemistry

The possibility that stable complexes may be formed between alpha particles (He²⁺) and small molecules is investigated using QCISD quantum mechanical calculations. Implications for their presence in the terrestrial atmosphere and/or in interstellar space are discussed. Figure Optimized structure of a stable H₂OHe²⁺ complex     

Modeling study of the influences of the aromatic transitions and the local environment on the far-UV rotational strengths in TEM-1 β-lactamase

Rotational strengths in the far-UV of TEM-1 β-lactamase have been investigated with two theoretical models based on the matrix method. The first model excludes, and a second includes, effects of the local electrostatic interactions on the chromophore energies. Special attention is given to the contributions of the aromatic side-chain chromophores, and the mechanisms of generation of rotational strengths are analyzed. The sensitivity of the computational models with respect to the structural changes of the protein are discussed. Figure Structure of TEM-1 β-lactamase. Both domains—α and αβ, the secondary structural elements and the aromatic and disulfide chromophores are shown