An in silico approach to design peptide mimetics based on docking and molecular dynamics simulation of EGFR–matuzumab complex

Epidermal growth factor receptor (EGFR) plays an essential role in anticancer therapy. Matuzumab is an antibody for the treatment of colorectal, lung and stomach cancer. Matuzumab binds efficiently to EGFR and blocks its phosphorylation. The recent clinical successes have established application of peptides for cancer treatment. The present contribution introduces an in silico approach to design peptides based on molecular dynamics simulation (MDs) of the matuzumab-EGFR complex in water environment. Moreover, principal component analysis has been used to select multiple conformations of the complex in MDs for designing the peptides. The paratope and epitope in each conformation of the complex were determined, and the alanine scanning was used to identify the hot spots of EGFR conformers. The conformations of the peptides were optimized using PEP-FOLD server and MDs. The selected conformations were analyzed in a docking study to realize the binding site of the EGFR. Finally, pharmokinetics properties of the peptides were calculated. The designed oligopeptides were EWRSYYYWH, YYYWHNEWN, YYYWHNEWS and HNHSRNYGS with a higher affinity to the EGFR relative to the previously reported peptides. The newly designed peptides were investigated for their in vivo toxicities on rats, and all of them were non-toxic.     

The molecular conformation of butyl acrylate – A vibrational spectroscopy and computational study

Potential energy curves allow us to probe the flexibility of butyl acrylate molecule. We found two local minima belonging to C_s symmetry for s-cis and s-trans conformations. The optimized geometries at RHF and DFT using extended basis set are in good agreement with electron diffraction data of methyl acrylate, and the s-cis is the most stable form. Ab initio calculations of harmonic frequencies at the fully optimized geometries of the planar s-cis and s-trans conformers have been performed at the DFT//B3LYP/6-311+G** level of theory. Scaled harmonic frequencies and potential energy distribution are used for the assignment of the experimental IR and Raman bands. We noticed an acceptable qualitative agreement between the experimental and the computed spectra.     

Ab initio molecular dynamics — Applications to the molecular and solid state physics of phosphorus

Summary We review combined molecular dynamics (MD) and density functional (DF) simulations and their applicability in chemistry and physics. This method (also termedab initio MD, first principles MD or Car-Parrinello method) exhibits characteristic strengths and weaknesses, and we demonstrate both in a set of typical example applications from molecular physics (phosphorus clusters) and solid state physics/chemistry (liquid phosphorus). Dynamical, finite temperature, simulations deriving interatomic forces from state-of-the-art density functional calculations represent a substantial advance over both (i) traditional pointwise total energy and electronic band structure calculations and (ii) classical MD simulations with empirical or semi-empirical forces, and have already yielded qualitatively new insights in several fields.     

Observation of ultrafast NH3 (Ã) state relaxation dynamics using a combination of time-resolved photoelectron spectroscopy and photoproduct detection

The ultrafast excited state relaxation of ammonia is investigated by resonantly exciting specific vibrational modes of the electronically excited NH(3) (?) state using three complementary femtosecond (fs) pump-probe techniques: time-resolved photoelectron, ion-yield and photofragment translational spectroscopy. Ammonia can be seen as a prototypical system for studying non-adiabatic dynamics and therefore offers a benchmark species for demonstrating the advantages of combining the aforementioned techniques to probe excited state dynamics, whilst simultaneously illuminating new aspects of ammonia's photochemistry. Time-resolved photoelectron spectroscopy (TRPES) provides direct spectroscopic evidence of σ* mediated relaxation of the NH(3) (?) state which manifests itself as coupling of the umbrella (ν(2)) and symmetric N-H stretch (ν(1)) modes in the photoelectron spectra. Time-resolved ion yield (TRIY) and time-resolved photofragment translation spectroscopy (TRPTS) grant a measure of the dissociation dynamics through analysis of the H and NH(2) photodissociation co-fragments. Initial vibrational level dependent TRIY measurements reveal photoproduct formation times of between 190 and 230 fs. Measurement of H-atom photoproduct kinetic energies enables investigation into the competition between adiabatic and non-adiabatic dissociation channels at the NH(3) (?)/NH(3) (X?) conical intersection and has shown that upon non-adiabatic dissociation into NH(2) (X?) + H, the NH(2) (X[combining tilde]) fragment is predominantly generated with significant fractions of internal vibrational energy.     

Binding of biguanides to β-lactoglobulin: molecular-docking and molecular dynamics simulation studies

Biguanides are a class of drugs derived from biguanide and they are the most widely used drugs for diabetes mellitus or pre-diabetes treatment. An investigation of their interaction and a transport protein such as β-lactoglobulin (BLG) at atomic level could be a valuable factor in controlling their transport to biological sites. Molecular-docking and molecular dynamics simulation methods were used to study the interaction of metformin, phenformin and buformin as biguanides and BLG as transport protein. The molecular-docking results revealed that these biguanides bind to BLG and that the BLG affinity for binding the biguanides decreases in the following order: phenformin — buformin — metformin. The docking results also show the hydrophobic interactions to have a significant role in the BLG-biguanides complex stability. Analysis of molecular dynamic simulation trajectories shows that the root mean square deviation of various systems attained equilibrium and fluctuated around the mean value at various times. The time evolution of the radius of gyration and the total solvent-accessible surface of the protein showed that BLG and BLG-biguanide complexes became stable at approximately 2500 ps and that there was not any conformational change in the BLG-biguanide complexes. In addition, the profiles of atomic fluctuations show the rigidity of the ligand-binding site during the simulation.     

How homogeneous are the trehalose, maltose, and sucrose water solutions? An insight from molecular dynamics simulations

The structural properties resulting from the reciprocal influence between water and three well-known homologous disaccharides, namely, trehalose, maltose, and sucrose, in aqueous solutions have been investigated in the 4-66 wt % concentration range by means of molecular dynamics computer simulations. Hydration numbers clearly show that trehalose binds to a larger number of water molecules than do maltose or sucrose, thus affecting the water structure to a deeper extent. Two-dimensional radial distribution functions of trehalose solutions definitely reveal that water is preferentially localized at the hydration sites found in the trehalose dihydrate crystal, this tendency being enhanced when increasing trehalose concentration. Over a rather wide concentration range (4-49 wt %), the fluctuations of the radius of gyration and of the glycosidic dihedral angles of trehalose indicate a higher flexibility with respect to maltose and sucrose. At sugar concentrations between 33 and 66 wt %, the mean sugar cluster size and the number of sugar-sugar hydrogen bonds formed within sugar clusters reveal that trehalose is able to form larger clusters than sucrose but smaller than maltose. These features suggest that trehalose-water mixtures would be more homogeneous than the two others, thus reducing both desiccation stresses and ice formation.     

Structure and molecular dynamics of host–guest complexes of TEMPO with cucurbituryl: An ESR and DFT study

Host–guest complexes are of interest as promising nanodevices for molecular recognition and chemosensors. In this work, the structure and molecular dynamics of complexes of the nitroxyl radical TEMPO (I), as models of indicator and analyte, with cucurbituril CB[7] in solution and in the solid phase have been studied by ESR and DFT methods. The kinetic accessibility of the NO group of I for water-soluble reagents has been determined. By simulation of the ESR spectra of the complex, the rotational diffusion coefficients and the anisotropy of its rotation have been determined. To study the rotational mobility of the guest in the CB[7] cavity, solid solutions of I@CB[7] in the CB[7] matrix have been obtained. The ESR spectra indicate rapid jump-like rotation of I about an axis oriented along the normal to the CB[7] portals. The formation energy and the spatial structure of the complex have been calculated by the DFT method; a change in the spin density on the NO group with changing the orientation of I in the CB[7] cavity has been found.     

Does ℏ play a role in multidimensional spectroscopy? Reduced hierarchy equations of motion approach to molecular vibrations

To investigate the role of quantum effects in vibrational spectroscopies, we have carried out numerically exact calculations of linear and nonlinear response functions for an anharmonic potential system nonlinearly coupled to a harmonic oscillator bath. Although one cannot carry out the quantum calculations of the response functions with full molecular dynamics (MD) simulations for a realistic system which consists of many molecules, it is possible to grasp the essence of the quantum effects on the vibrational spectra by employing a model Hamiltonian that describes an intra- or intermolecular vibrational motion in a condensed phase. The present model fully includes vibrational relaxation, while the stochastic model often used to simulate infrared spectra does not. We have employed the reduced quantum hierarchy equations of motion approach in the Wigner space representation to deal with nonperturbative, non-Markovian, and nonsecular system-bath interactions. Taking the classical limit of the hierarchy equations of motion, we have obtained the classical equations of motion that describe the classical dynamics under the same physical conditions as in the quantum case. By comparing the classical and quantum mechanically calculated linear and multidimensional spectra, we found that the profiles of spectra for a fast modulation case were similar, but different for a slow modulation case. In both the classical and quantum cases, we identified the resonant oscillation peak in the spectra, but the quantum peak shifted to the red compared with the classical one if the potential is anharmonic. The prominent quantum effect is the 1-2 transition peak, which appears only in the quantum mechanically calculated spectra as a result of anharmonicity in the potential or nonlinearity of the system-bath coupling. While the contribution of the 1-2 transition is negligible in the fast modulation case, it becomes important in the slow modulation case as long as the amplitude of the frequency fluctuation is small. Thus, we observed a distinct difference between the classical and quantum mechanically calculated multidimensional spectra in the slow modulation case where spectral diffusion plays a role. This fact indicates that one may not reproduce the experimentally obtained multidimensional spectrum for high-frequency vibrational modes based on classical molecular dynamics simulations if the modulation that arises from surrounding molecules is weak and slow. A practical way to overcome the difference between the classical and quantum simulations was discussed.     

A graph‐theoretical approach to statistics and dynamics of tree‐like molecules

We present a new graphtheoretical method for calculating the dynamical and statistical properties of a Gaussian chain with various molecular architecture. The characteristic polynomial for its line graph, which has the bonds of a molecular graph as its beads with adjacency of bonds as in the graph, makes it possible to provide us with the general equation for calculating the radius of gyration of Gaussian chains and their relaxation spectra.     

An approach to the synthesis of 1,2λ-azaphosphinines

A novel approach to 1,2λ⁵-azaphosphinines has been elaborated. Aminophosphonium chlorides bearing a β-dialkylaminocrotonic nitrile residue react with N,N-dimethylformamide dimethylacetal to afford 1,2λ⁵-azaphosphinines.     

Illuminating the flesh of bone identification – An application of near infrared spectroscopy

Near infrared (NIR) reflectance spectroscopy coupled with chemometric analysis was evaluated as a non-destructive tool to discriminate skull bone samples from different animal species. In total 70 skull bones from animals of three classes (mammalians, avian and reptiles) were scanned in the wavelength range between 950 to 1650 nm. Principal component analysis (PCA) and partial least squares discriminant analysis (PLS-DA) were used to analyse the NIR spectra of the skull samples. Correct classification rates of 96% and 81% were obtained for the classification of skull bone samples according to avian and mammalian classes, respectively. Overall, a 91% correct classification rate was obtained for the classification of skull samples according to the class (mammalian and avian). This study demonstrates the potential of NIR spectroscopy coupled with chemometric as data processing, as a means of a rapid, non-destructive classification technique for skull bone samples.     

Ultrafast excited state dynamics and spectroscopy of 13,13'-diphenyl-β-carotene

Ultrafast transient broadband absorption spectroscopy based on the Pump-Supercontinuum Probe (PSCP) technique has been applied to characterize the excited state dynamics of the newly-synthesized artificial β-carotene derivative 13,13'-diphenyl-β-carotene in the wavelength range 340-770 nm with ca. 60 fs cross-correlation time after excitation to the S(2) state. The influence of phenyl substitution at the polyene backbone has been investigated in different solvents by comparing the dynamics of the internal conversion (IC) processes S(2)→ S(1) and S(1)→ S(0)* with results for β-carotene. Global analysis provides IC time constants and also time-dependent S(1) spectra demonstrating vibrational relaxation processes. Intramolecular vibrational redistribution processes are accelerated by phenyl substitution and are also solvent-dependent. DFT and TDDFT-TDA calculations suggest that both phenyl rings prefer an orientation where their ring planes are almost perpendicular to the plane of the carotene backbone, largely decoupling them electronically from the polyene system. This is consistent with several experimental observations: the up-field chemical shift of adjacent hydrogen atoms by a ring-current effect of the phenyl groups in the (1)H NMR spectrum, a small red-shift of the S(0)→ S(2)(0-0) transition energy in the steady-state absorption spectrum relative to β-carotene, and almost the same S(1)→ S(0)* IC time constant as in β-carotene, suggesting a similar S(1)-S(0) energy gap. The oscillator strength of the S(0)→ S(2) transition of the diphenyl derivative is reduced by ca. 20%. In addition, we observe a highly structured ground state bleach combined with excited state absorption at longer wavelengths, which is typical for an "S* state". Both features can be clearly assigned to absorption of vibrationally hot molecules in the ground electronic state S(0)* superimposed on the bleach of room temperature molecules S(0). The S(0)* population is formed by IC from S(1). These findings are discussed in detail with respect to alternative interpretations previously reported in the literature. Understanding the dynamics of this type of artificial phenyl-substituted carotene systems appears useful regarding their future structural optimization with respect to enhanced thermal stability while keeping the desired photophysical properties.     

Ab initio surface hopping excited-state molecular dynamics approach on the basis of spin–orbit coupled states: An application to the A-band photodissociation of CH3I

Ab initio molecular dynamics approach has been extended to multi-state dynamics on the basis of the spin–orbit coupled electronic states that are obtained through diagonalization of the spin–orbit coupling matrix with the multi-state second-order multireference perturbation theory energies in diagonal elements and the spin–orbit coupling terms at the state-averaged complete active space self-consistent field level in off-diagonal elements. Nonadiabatic transitions over the spin–orbit coupled states were taken into account explicitly by a surface hopping scheme with utilizing the nonadiabatic coupling terms calculated by numerical differentiation of the spin–orbit coupled wavefunctions and analytical nonadiabatic coupling terms. The present method was applied to the A-band photodissociation of methyl iodide, CH₃I + hv → CH₃ + I (²P_3/2)/I* (²P_1/2), for which a pioneering theoretical work was reported by Amatatsu, Yabushita, and Morokuma. The present results reproduced well the experimental branching ratio and energy distributions in the dissociative products. © 2018 Wiley Periodicals, Inc.     

Forcefield evaluation and accelerated molecular dynamics simulation of Zn(II) binding to N-terminus of amyloid-β

We report conventional and accelerated molecular dynamics simulation of Zn(II) bound to the N-terminus of amyloid-β. By comparison against NMR data for the experimentally determined binding mode, we find that certain combinations of forcefield and solvent model perform acceptably in describing the size, shape and secondary structure, and that there is no appreciable difference between implicit and explicit solvent models. We therefore used the combination of ff14SB forcefield and GBSA solvent model to compare the result of different binding modes of Zn(II) to the same peptide, using accelerated MD to enhance sampling and comparing the free peptide simulated in the same way. We show that Zn(II) imparts significant rigidity to the peptide, disrupts the secondary structure and pattern of salt bridges seen in the free peptide, and induces closer contact between residues. Free energy surfaces in 1 or 2 dimensions further highlight the effect of metal coordination on peptide’s spatial extent. We also provide evidence that accelerated MD provides improved sampling over conventional MD by visiting as many or more configurations in much shorter simulation times.     

An organocatalytic approach to enantiomerically enriched α-arylcyclohexenones and cyclohexanones

The presence of a p-nitrophenyl group converts acetone into an excellent and versatile nucleophile in organocatalytic processes, able to react with α,β-unsaturated aldehydes affording β-substituted α-arylcyclohexenones via a Michael reaction/aldol reaction/dehydration sequence, which occurs in good yields, ee up to 96% and complete diastereoselectivity. The resulting compounds are excellent synthons for the diastereoselective preparation of a variety of synthetically useful polysubstituted cyclohexanones and derivatives.     

Two-dimensional functional molecular nanoarchitectures – Complementary investigations with scanning tunneling microscopy and X-ray spectroscopy

Functional molecular nanoarchitectures (FMNs) are highly relevant for the development of future nanotechnology devices. Profound knowledge about the atomically controlled construction of such nanoscale assemblies is an indispensable requirement to render the implementation of such components into a real product successful. For exploiting their full potential the architectures’ functionalities have to be characterized in detail including the ways to tailor them. In recent years a plethora of sophisticated constructs were fabricated touching a wide range of research topics.     

Inertia-corrected budó treatment of dielectric relaxation in polar molecules: Application to the fir spectrum of acetonttrile and hexanone-2

The theory of dielectric relaxation of an assembly of molecules with neareit-neighbour dipole-dipole coupling, originally developed by Budó, is extended to include inertial effects. This yields an orientational correlation function that gives rise to Debye-type absorption in the microwave region and resonance absorption in the FIR region. The results are formally similar to the itinerant-oscillator model when the outer cage in that model carries a dipole moment. The results compare favourably with experimental observations on acetonitrile and hexanone-2.     

Features of molecular light scattering and structure of the chlorobenzene–o-dichlorobenzene solutions

Structural Chemistry - The total light scattering coefficient, degree of depolarization, refractive index, and density were measured in chlorobenzene–o-dichlorobenzene solutions. The...     

Tandem β-fragmentation-intramolecular functionalization of alkoxyradicals. An approach to the synthesis of a and a'rings of limonin

A tandem β-fragmentation-intramolecular functionalization reaction is observed by photolysis of steroidal lactols in the presence of several oxidation agents under oxygen. An application of this reaction to the synthesis of A and A'rings of limonin (1) is described.     

An approach to the synthesis of α-l-fucopyranosyl phosphoric mono- and diesters via phosphite intermediates

The reagent chloro-β-cyanoethyl-N,N-diisopropylamino-phosphoramidite reacts smoothly with the anomeric hydroxyl group of a properly protected (benzyl) α-L-fucopyranose to afford a relatively stable phosphite intermediate in high yield. The latter can easily be converted into valuable α-L-fucopyranosyl phosphoric mono- and diesters.