New insight into the IR-spectra/structure relationship in amyloid fibrils: a theoretical study on a prion peptide

Molecular-level structural information on amyloid aggregates is of great importance for the understanding of protein-misfolding-related deseases. Nevertheless, this kind of information is experimentally difficult to obtain. In this work, we used molecular dynamics (MD) simulations combined with a mixed quantum mechanics/molecular mechanics theoretical methodology, the perturbed matrix method (PMM), in order to study the amide I' IR spectrum of fibrils formed by a short peptide, the H1 peptide, derived from residues 109 through 122 of the Syrian hamster prion protein. The PMM/MD approach allows isolation of the amide I' signal arising from any desired peptide group of the polypeptide chain and quantification of the effect of the excitonic coupling on the frequency position. The calculated single-residue signals were found to be in good agreement with the experimental site-specific spectra obtained by means of isotope-labeled IR spectroscopy, providing a means for their interpretation at the molecular level. In particular, our results confirm the experimental hypothesis that residues ala117 are aligned in all strands and that the alignment gives rise to a red shift of the corresponding site-specific amide I' mode due to strong excitonic coupling among the ala117 peptide groups. In addition, our data show that a red shift of the amide I' band due to strong excitonic coupling can also occur for amino acids adjacent in sequence to the aligned ones. Thus, a red shift of the signal of a given isotope-labeled amino acid does not necessarily imply that the peptide groups under consideration are aligned in the β-sheet.     

Fine‐Tuning of Charge‐Conversion Polymer Structure for Efficient Endosomal Escape of siRNA‐Loaded Calcium Phosphate Hybrid Micelles

For efficient delivery of siRNA into the cytoplasm, a smart block copolymer of poly(ethylene glycol) and charge‐conversion polymer (PEG‐CCP) is developed by introducing 2‐propionic‐3‐methylmaleic (PMM) amide as an anionic protective group into side chains of an endosome‐disrupting cationic polyaspartamide derivative. The PMM amide moiety is highly susceptible to acid hydrolysis, generating the parent cationic polyaspartamide derivative at endosomal acidic pH 5.5 more rapidly than a previously synthesized cis‐aconitic (ACO) amide control. The PMM‐based polymer is successfully integrated into a calcium phosphate (CaP) nanoparticle with siRNA, constructing PEGylated hybrid micelles (PMM micelles) having a sub‐100 nm size at extracellular neutral pH 7.4. Ultimately, PMM micelles achieve the significantly higher gene silencing efficiency in cultured cancer cells, compared to ACO control micelles, probably due to the efficient endosomal escape of the PMM micelles. Thus, it is demonstrated that fine‐tuning of acid‐labile structures in CCP improves the delivery performance of siRNA‐loaded nanocarriers.

     

A polarizable force field for computing the infrared spectra of the polypeptide backbone

The shapes of the amide bands in the infrared (IR) spectra of proteins and peptides are caused by electrostatically coupled vibrations within the polypeptide backbone and code the structures of these biopolymers. A structural decoding of the amide bands has to resort to simplified models because the huge size of these macromolecules prevents the application of accurate quantum mechanical methods such as density functional theory (DFT). Previous models employed transition-dipole coupling methods that are of limited accuracy. Here we propose a concept for the computation of protein IR spectra, which describes the molecular mechanics (MM) of polypeptide backbones by a polarizable force field of "type II". By extending the concepts of conventional polarizable MM force fields, such a PMM/II approach employs field-dependent parameters not only for the electrostatic signatures of the molecular components but also for the local potentials modeling the stiffness of chemical bonds with respect to elongations, angle deformations, and torsions. Using a PMM/II force field, the IR spectra of the polypeptide backbone can be efficiently calculated from the time dependence of the backbone's dipole moment during a short (e.g., 100 ps) MD simulation by Fourier transformation. PMM/II parameters are derived for harmonic bonding potentials of amide groups in polypeptides from a series of DFT calculations on the model molecule N-methylacetamide (NMA) exposed to homogeneous external electric fields. The amide force constants are shown to vary by as much as 20% for relevant field strengths. As a proof of principle, it is shown that the large solvatochromic effects observed in the IR spectra of NMA upon transfer from the gas phase into aqueous solution are not only excellently reproduced by DFT/MM simulations but are also nicely modeled by the PMM/II approach. The tasks remaining for a proof of practice are specified.     

Quantum-mechanical calculation of the reactions D + FH(ν = 0, 1, 2) → DF(ν′) + H and H + FD(ν = 0, 1, 2, 3) → HF(ν′) + D on a realistic potential energy surface

Collinear (two-mathematical-dimensional (2MD)) coupled-channel quantum-mechanical calculations have been performed on the reactions D + FH(ν = 0, 1, 2) → DF(ν′) + H and H + FD(ν = 0, 1, 2, 3) → HF(ν′) + D on a potential energy surface with a 40 kcal/mole barrier to exchange. This barrier height is close to that predicted by ab initio calculations and suggested by experiments. The relative effectiveness of reagent vibrational and translational excitation to promote reaction is considered. A one-mathematical-dimensional (1MD) model for these reactions is constructed and is shown to work very well for the D + FH reaction at high temperatures, and less well for that reaction at lower temperatures as well as for the reverse H + FD reaction. Possible reasons for the breakdowns of this model are discussed.     

Tyrosine absorption spectroscopy: Backbone protonation effects on the side chain electronic properties

The UV–vis spectrum of Tyrosine and its response to different backbone protonation states have been studied by applying the Perturbed Matrix Method (PMM) in conjunction with molecular dynamics (MD) simulations. Herein, we theoretically reproduce the UV–vis absorption spectrum of aqueous solution of Tyrosine in its zwitterionic, anionic and cationic forms, as well as of aqua‐p‐Cresol (i.e., the moiety that constitutes the side chain portion of Tyrosine). To achieve a better accuracy in the MD sampling, the Tyrosine Force Field (FF) parameters were derived de novo via quantum mechanical calculations. The UV–vis absorption spectra are computed considering the occurring electronic transitions in the vertical approximation for each of the chromophore configurations sampled by the classical MD simulations, thus including the effects of the chromophore semiclassical structural fluctuations. Finally, the explicit treatment of the perturbing effect of the embedding environment permits to fully model the inhomogeneous bandwidth of the electronic spectra. Comparison between our theoretical–computational results and experimental data shows that the used model captures the essential features of the spectroscopic process, thus allowing to perform further analysis on the strict relationship between the quantum properties of the chromophore and the different embedding environments. © 2018 Wiley Periodicals, Inc.     

Free-energy based pair-additive potentials for bulk Ni-Al systems: Application to study Ni-Al reactive alloying

We present new numerical pair-additive Al, Ni, and Al-Ni potentials by force-matching (FM) ionic force and virial data from single (bulk liquid) phase ab initio molecular dynamics (MD) simulations using the Born-Oppenheimer method. The potentials are represented by piece-wise functions (splines) and, therefore, are not constrained to a particular choice of analytical functional form. The FM method with virial constraint naturally yields a potential which maps out the ionic free-energy surface of the reference ensemble. To further improve the free energetics of the FM ensemble, the FM procedure is modified to bias the potentials to reproduce the experimental melting temperatures of the reference (FCC-Al, FCC-Ni, B2-NiAl) phases, the only macroscopic data included in the fitting set. The performance of the resultant potentials in simulating bulk metallic phases is then evaluated. The new model is applied to perform MD simulations of self-propagating exothermic reaction in Ni-Al bilayers at P = 0-5 GPa initiated at T = 1300 K. Consistent with experimental observations, the new model describes realistically a sequence of peritectic phase transformations throughout the reaction and at a realistic rate. The reaction proceeds through interlayer diffusion of Al and Ni atoms at the interface with formation of B2-NiAl in the Al melt. Such material responses have, in the past, been proven to be difficult to observe with then-existing potentials.     

The reversible opening of water channels in cytochrome C modulates the heme iron reduction potential

Dynamic protein-solvent interactions are fundamental for life processes, but their investigation is still experimentally very demanding. Molecular dynamics simulations up to hundreds of nanoseconds can bring to light unexpected events even for extensively studied biomolecules. This paper reports a combined computational/experimental approach that reveals the reversible opening of two distinct fluctuating cavities in Saccharomyces cerevisiae iso-1-cytochrome c. Both channels allow water access to the heme center. By means of a mixed quantum mechanics/molecular dynamics (QM/MD) theoretical approach, the perturbed matrix method (PMM), that allows to reach long simulation times, changes in the reduction potential of the heme Fe(3+)/Fe(2+) couple induced by the opening of each cavity are calculated. Shifts of the reduction potential upon changes in the hydration of the heme propionates are observed. These variations are relatively small but significant and could therefore represent a tool developed by cytochrome c for the solvent driven, fine-tuning of its redox functionality.     

Digital image colorimetry method for determination of glucose using silver nanoparticles immobilized into polymethacrylate matrix

We suggest Ag⁰ nanoparticles immobilized into transparent polymethacrylate matrix (PMM–Ag⁰) as a simple colorimetric sensor for determination of glucose. We demonstrate the capabilities of a smartphone to process the images and further analyze the information obtained by determination of glucose using PMM–Ag⁰ sensor. The method can be employed for glucose concentrations of 0.1–4.3 mmol dm⁻³, while its detection limit is 0.05 mmol dm⁻³.     

Identification of 2D-gel proteins: a comparison of MALDI/TOF peptide mass mapping to mu LC-ESI tandem mass spectrometry

A comparative analysis of protein identification for a total of 162 protein spots separated by two-dimensional gel electrophoresis from two fully sequenced archaea, Methanococcus jannaschii and Pyrococcus furiosus, using MALDI-TOF peptide mass mapping (PMM) and mu LC-MS/MS is presented. 100% of the gel spots analyzed were successfully matched to the predicted proteins in the two corresponding open reading frame databases by mu LC-MS/MS while 97% of them were identified by MALDI-TOF PMM. The high success rate from the PMM resulted from sample desalting/concentrating with ZipTip(C18) and optimization of several PMM search parameters including a 25 ppm average mass tolerance and the application of two different protein molecular weight search windows. By using this strategy, low-molecular weight (<23 kDa) proteins could be identified unambiguously with less than 5 peptide matches. Nine percent of spots were identified as containing multiple proteins. By using mu LC-MS/MS, 50% of the spots analyzed were identified as containing multiple proteins. mu LC-MS/MS demonstrated better protein sequence coverage than MALDI-TOF PMM over the entire mass range of proteins identified. MALDI-TOF and PMM produced unique peptide molecular weight matches that were not identified by mu LC-MS/MS. By incorporating amino acid sequence modifications into database searches, combined sequence coverage obtained from these two complimentary ionization methods exceeded 50% for approximately 70% of the 162 spots analyzed. This improved sequence coverage in combination with enzymatic digestions of different specificity is proposed as a method for analysis of post-translational modification from 2D-gel separated proteins.     

The Strength of the Macromonomer Strategy for Complex Macromolecular Architecture: Molecular Characterization,Properties and Applications of Polymacromonomers

The efficiency of the macromonomer (MM) synthetic strategy for the creation of nonlinear complex macromolecular architectures (miktoarm stars, α,ω‐branched polymers, random/exact comb and graft copolymers, dendritic polymers, molecular brushes) is reviewed. In addition, the solution/bulk properties and the potential applications of polymacromonomers (PMM), as well as new synthetic ideas are presented. The synthesis of macromonomers and living polymacromonomers in situ leads to many novel linear and nonlinear structures, as for example PMM‐b‐PS‐b‐PMM, (PS)₂PMM. The use of multichlorosilylstyrenes as monomer/linking agents opens new ways for structures with multichain macromonomeric building blocks.

The use of multichlorosilylstyrenes as monomer/linking agents opens new ways for structures having multichain macromonomeric building blocks.     

Effect of local strain on the reactivity of carbon nanotubes

The heats of addition of H atom and Me^· radical to carbon atoms of a capped (10,10)-nanotube were calculated by the molecular dynamics (MD) method with Brenner"s potential. According to calculations, the reaction heats linearly depend on the pyramidalization angle, which is a quantitative measure of the local curvature and strain in the planar carbon sheet in the vicinity of the reaction center. Depending on the pyramidalization angle (0—20°), the change in the reaction energy can reach 1 eV. Comparison of the results obtained for a model reaction CH₃ ^· + H^· CH₄ using the ab initio approach and MD simulations with Brenner"s potential shows that this potential can be used in studies of the effect of pyramidalization of the carbon center on its reactivity.     

Statistical mechanical modelling of chemical reactions in complex systems: the kinetics of the Haem carbon monoxide binding–unbinding reaction in Myoglobin

The free energy profile and the (classical) kinetics of chemical reactions in (soft) condensed phase may be well modelled theoretically by means of molecular dynamics simulations, the perturbed matrix method (PMM) and statistical mechanics, as we provided in previous articles. In this paper, we describe the theoretical framework, discussing thoroughly its crucial points, and apply the model to an important biochemical reaction: the Haem carbon monoxide binding–unbinding reaction in Myoglobin, specifically investigating the reaction step involving the carbon–iron chemical bond formation (disruption) which is of particular biochemical interest.     

Theoretical studies of solid bicyclo-HMX: effects of hydrostatic pressure and temperature

On the basis of density functional theory (DFT) and molecular dynamics (MD), the structural, electronic, and mechanical properties of the energetic material bicyclo-HMX have been studied. The crystal structure optimized by the LDA/CA-PZ method compares well with the experimental data. Band structure and density of states calculations indicate that bicyclo-HMX is an insulator with the band gap of ca. 3.4 eV and the N-NO(2) bond is the reaction center. The pressure effect on the bulk structure and properties has been investigated in the range of 0-400 GPa. The crystal structure and electronic character change slightly as the pressure increases from 0 to 10 GPa; when the pressure is over 10 GPa, further increment of the pressure determines significant changes of the structures and large broadening of the electronic bands together with the band gap decreasing sharply. There is a larger compression along the c-axis than along the a- and b-axes. To investigate the influence of temperature on the bulk structure and properties, isothermal-isobaric MD simulations are performed on bicyclo-HMX in the temperature range of 5-400 K. It is found that the increase of temperature does not significantly change the crystal structure. The thermal expansion coefficients calculated for the model indicate anisotropic behavior with slightly larger expansion along the a- and c-axes than along the b-axis.     

Acetylcholinesterase: mechanisms of covalent inhibition of wild-type and H447I mutant determined by computational analyses

The reaction mechanisms of two inhibitors TFK+ and TFK0 binding to both the wild-type and H447I mutant mouse acetylcholinesterase (mAChE) have been investigated by using a combined ab initio quantum mechanical/molecular mechanical (QM/MM) approach and classical molecular dynamics (MD) simulations. In the wild-type mAChE, the binding reactions of TFK+ and TFK0 are both spontaneous processes, which proceed through the nucleophilic addition of the Ser203-Ogamma to the carbonyl-C of TFK+ or TFK0, accompanied with a simultaneous proton transfer from Ser203 to His447. No barrier is found along the reaction paths, consistent with the experimental reaction rates approaching the diffusion-controlled limit. By contrast, TFK+ binding to the H447I mutant may proceed with a different reaction mechanism. A water molecule takes over the role of His447 and participates in the bond breaking and forming as a "charge relayer". Unlike in the wild-type mAChE case, Glu334, a conserved residue from the catalytic triad, acts as a catalytic base in the reaction. The calculated energy barrier for this reaction is about 8 kcal/mol. These predictions await experimental verification. In the case of the neutral ligand TFK0, however, multiple MD simulations on the TFK0/H447I complex reveal that none of the water molecules can be retained in the active site as a "catalytic" water. Furthermore, our alchemical free energy calculation also suggests that the binding of TFK0 to H447I is much weaker than that of TFK+. Taken together, our computational studies confirm that TFK0 is almost inactive in the H447I mutant and also provide detailed mechanistic insights into the experimental observations.     

Molecular dynamics investigations of the dissociation of SiO2 on an ab initio potential energy surface obtained using neural network methods

The neural network (NN) procedure to interpolate ab initio data for the purpose of molecular dynamics (MD) simulations has been tested on the SiO(2) system. Unlike other similar NN studies, here, we studied the dissociation of SiO(2) without the initial use of any empirical potential. During the dissociation of SiO(2) into Si+O or Si+O(2), the spin multiplicity of the system changes from singlet to triplet in the first reaction and from singlet to pentet in the second. This paper employs four potential surfaces. The first is a NN fit [NN(STP)] to a database comprising the lowest of the singlet, triplet, and pentet energies obtained from density functional calculations in 6673 nuclear configurations. The other three potential surfaces are obtained from NN fits to the singlet, triplet, and pentet-state energies. The dissociation dynamics on the singlet-state and NN(STP) surfaces are reported. The results obtained using the singlet surface correspond to those expected if the reaction were to occur adiabatically. The dynamics on the NN(STP) surface represent those expected if the reaction follows a minimum-energy pathway. This study on a small system demonstrates the application of NNs for MD studies using ab initio data when the spin multiplicity of the system changes during the dissociation process.     

Molecular simulations of outersphere reorganization energies in polar and quadrupolar solvents. The case of intramolecular electron and hole transfer

Outersphere reorganization energies (lambda) for intramolecular electron and hole transfer are studied in anion- and cation-radical forms of complex organic substrates (p-phenylphenyl-spacer-naphthyl) in polar (water, 1,2-dichloroethane, tetrahydrofuran) and quadrupolar (supercritical CO2) solvents. Structure and charge distributions of solute molecules are obtained at the HF/6-31G(d,p) level. Standard Lennard-Jones parameters for solutes and the nonpolarizable simple site-based models of solvents are used in molecular dynamics (MD) simulations. Calculation of lambda is done by means of the original procedure, which treats electrostatic polarization of a solvent in terms of a usual nonpolarizable MD scheme supplemented by scaling of reorganization energies at the final stage. This approach provides a physically relevant background for separating inertial and inertialless polarization responses by means of a single parameter epsilon(infinity), optical dielectric permittivity of the solvent. Absolute lambda values for hole transfer in 1,2-dichloroethane agree with results of previous computations in terms of the different technique (MD/FRCM, Leontyev, I. V.; et al. Chem. Phys. 2005, 319, 4). Computed lambda values for electron transfer in tetrahydrofuran are larger than the experimental values by ca. 2.5 kcal/mol; for the case of hole transfer in 1,2-dichloroethane the discrepancy is of similar magnitude provided the experimental data are properly corrected. The MD approach gives nonzero lambda values for charge-transfer reaction in supercritical CO2, being able to provide a uniform treatment of nonequilibrium solvation phenomena in both quadrupolar and polar solvents.     

O2 interaction and reactivity on a model hydroxylated rutile(110) surface

Recently several theoretical studies have examined oxygen adsorption on the clean, reduced TiO2(110) surface. However the photocatalytic behavior of TiO2 and the scavenging ability of oxygen are known to be influenced by the presence of surface hydroxyls. In this paper the chemistry of O2 on the hydroxylated TiO2 surface is investigated by means of first-principles total energy calculations and molecular dynamics (MD) simulations. The MD trajectories show a direct, spontaneous reaction between O2 and the surface hydroxyls, thus supporting the experimental hypothesis that the reaction does not necessarily pass through a chemisorbed O2 state. Following this reaction, the most stable chemisorbed intermediates are found to be peroxide species HO2 and H2O2. Although these intermediates are very stable on the short time scale of MD simulations, the energetics suggests that their further transformation is connected to a new 300 K feature observed in the experimental water temperature programmed desorption (TPD) spectrum. The participation of two less stable intermediate states, involving terminal hydroxyls and/or chemisorbed water plus oxygen adatoms, to the desorption process, is not supported by the total energy calculations. Analysis of the projected density of states, however, suggests the possibility that these intermediates have a role in completing the surface oxidation immediately before desorption.     

A critical look at the definition of multidimensional separations

Multidimensional (MD) separations, especially comprehensive two-dimensional (2D) separations such as comprehensive 2D LC (LC × LC), and comprehensive 2D GC (GC × GC), are potentially powerful separation techniques. It is important to have a clear definition of MD techniques to better understand the scope and boundaries of the subject. Widely accepted definitions of MD Separations have their roots in the definition proposed by Giddings. Giddings also added several comments that clarified the scope of his definition. However, some researchers extend Giddings’ definitions beyond their intended scope. Doing so disqualifies such comprehensive 2D techniques as LC × LC, GC × GC and 2D TLC from being considered as 2D techniques. In other instances, extended treatment of Giddings’ definition is used as a basis to justify design-parameters of comprehensive 2D separations despite the fact that these parameters lead to sub-optimal implementations. We believe that the shortcomings in the definition and its popular interpretations are serious enough to warrant attention, especially by those interested in designing optimal instrumentation for MD separations like comprehensive 2D GC. After discussion of the weaknesses in the currently used definitions, we propose to define n-dimensional analysis as one that generates n-dimensional displacement information. We believe that this definition captures the spirit of Giddings’ definition while avoiding the problems associated with its popular interpretations.