Valine Dipeptide Research Articles

CATBOSS: Cluster Analysis of Trajectories Based on Segment Splitting.

Molecular dynamics (MD) simulations are an exceedingly and increasingly potent tool for molecular behavior prediction and analysis. However, the enormous wealth of data generated by these simulations can be difficult to process and render in a human-readable fashion. Cluster analysis is a commonly used way to partition data into structurally distinct states. We present a method that improves on the state of the art by taking advantage of the temporal information of MD trajectories to enable more accurate clustering at a lower memory cost. To date, cluster analysis of MD simulations has generally treated simulation snapshots as a mere collection of independent data points and attempted to separate them into different clusters based on structural similarity. This new method, cluster analysis of trajectories based on segment splitting (CATBOSS), applies density-peak-based clustering to classify trajectory segments learned by change detection. Applying the method to a synthetic toy model as well as four real-life data sets–trajectories of MD simulations of alanine dipeptide and valine dipeptide as well as two fast-folding proteins–we find CATBOSS to be robust and highly performant, yielding natural-looking cluster boundaries and greatly improving clustering resolution. As the classification of points into segments emphasizes density gaps in the data by grouping them close to the state means, CATBOSS applied to the valine dipeptide system is even able to account for a degree of freedom deliberately omitted from the input data set. We also demonstrate the potential utility of CATBOSS in distinguishing metastable states from transition segments as well as promising application to cases where there is little or no advance knowledge of intrinsic coordinates, making for a highly versatile analysis tool.

Kinetic Hydrate Inhibition of Glycyl-valine-Based Alternating Peptoids with Tailor-Made N-Substituents

A series of alternating peptides with glycine-N-substituted valine dipeptide repeating units were synthesized. The N-substitution included methyl, ethyl, n-propyl, and hydroxyl groups. The performance of the polypeptides as kinetic hydrate inhibitors (KHIs) was evaluated in high pressure rocking cells with a synthetic natural gas mixture using the slow constant cooling method. All the polypeptides gave better KHI effect than a low molecular weight poly(N-vinylpyrrolidone). The polypeptide with N-substituted n-propyl groups, PA-Pep, performed the best, the same as a commercial poly(N-vinyl caprolactam) (PVCap) at the same concentration. The KHI performance of PA-Pep improved as the concentration of the solution was increased from 1000 to 5000 ppm. At 5000 ppm the average (10 experiments) onset temperature for hydrate formation was 9.8 °C (ca. ΔT = 10.4 °C).

Protective effects of antioxidant egg-chalaza hydrolysates against chronic alcohol consumption-induced liver steatosis in mice.

Reactive oxygen species (ROS) overproduction is highly related to some human chronic diseases. There are approximately 400 metric tons of chalazae produced yearly after the processing of the liquid-egg production, which are disposed of as waste. The objectives of this study were to look for the optimal production condition of antioxidant crude chalaza hydrolysates and evaluate the in vivo antioxidant capacity via a chronic alcohol consumption mouse model. Antioxidant crude chalaza hydrolysates (CCH-As) could be produced by protease A at 1:100 ratio (w/w) and 0.5 h hydrolytic period. After our analyses, CCH-As were rich in leucine, arginine, phenylalanine, valine, lysine and antioxidant dipeptides (anserine and carnosine), and the major molecular masses were lower than 15 kDa. Regarding protective effects of CCH-As against oxidative damage in alcoholic-liquid-diet-fed mice, alcohol-fed mice had lower (P < 0.05) liver antioxidant capacities, and higher (P < 0.05) liver lipid contents, serum lipid/liver damage indices and IL-1β/IL-6 values. CCH-A supplementation reversed (P < 0.05) liver antioxidant capacities and reduced (P < 0.05) serum/liver lipids in alcohol-fed mice, which may result from increased (P < 0.05) fecal lipid output, upregulated (P < 0.05) fatty acid β-oxidation and downregulated (P < 0.05) lipogenesis in the liver. Taken together, this CCH-A should benefit the liquid-egg industry, while also offering consumers a choice of healthy ingredients from animal sources. © 2018 Society of Chemical Industry.

Girsanov reweighting for path ensembles and Markov state models.

The sensitivity of molecular dynamics on changes in the potential energy function plays an important role in understanding the dynamics and function of complex molecules. We present a method to obtain path ensemble averages of a perturbed dynamics from a set of paths generated by a reference dynamics. It is based on the concept of path probability measure and the Girsanov theorem, a result from stochastic analysis to estimate a change of measure of a path ensemble. Since Markov state models (MSMs) of the molecular dynamics can be formulated as a combined phase-space and path ensemble average, the method can be extended to reweight MSMs by combining it with a reweighting of the Boltzmann distribution. We demonstrate how to efficiently implement the Girsanov reweighting in a molecular dynamics simulation program by calculating parts of the reweighting factor "on the fly" during the simulation, and we benchmark the method on test systems ranging from a two-dimensional diffusion process and an artificial many-body system to alanine dipeptide and valine dipeptide in implicit and explicit water. The method can be used to study the sensitivity of molecular dynamics on external perturbations as well as to reweight trajectories generated by enhanced sampling schemes to the original dynamics.

Asymmetric synthesis of quaternary aryl amino acid derivatives via a three-component aryne coupling reaction

A method was developed for the synthesis of α-alkyl, α-aryl-bislactim ethers in good to excellent yields and high diastereoselectivities, consisting of a facile one-pot procedure in which the aryl group is introduced by means of a nucleophilic addition to benzyne and the alkyl group by alkylation of a resultant benzylic anion. Hydrolysis of the sterically less hindered adducts gave the corresponding quaternary amino acids with no racemization, whereas hydrolytic ring opening gave the corresponding valine dipeptides from bulkier bislactims.

L-Valine Dipeptide Organocatalysts with Two Amide Units for the Direct Asymmetric Aldol Reaction in Brine

A series of valine dipeptide organocatalysts containing a primary amine group and two amide units have been developed and evaluated in the direct asymmetric intermolecular aldol reaction of 4-nitrobenzaldehyde and cyclohexanone. When 2,4-dinitrophenol (DNP) was used as an acidic additive, the catalyzed reactions of various aldehydes and ketones gave the corresponding aldol products with moderate to high enantioselectivities (up to 95%) and diastereoselectivities (up to >99/1, anti/syn) in the presence of 3c in brine. .

Stereoselective synthesis of β-substituted- l-threonines from enantiopure 5-acetyl-2-isoxazolines

Enantiomerically pure, 3-methyl- or 3-ethoxycarbonyl-substituted (5 S)- and (5 R)-5-acetyl-2-isoxazolines were obtained from the corresponding racemic mixtures by means of an enzymatic reduction with baker’s yeast, followed by the separation of the enantiopure syn- and anti-alcohols and oxidation of the alcohol group. The reaction between these ketones and (2 R)- Schöllkopf’s bislactim ether azaenolate was studied: using (5 S)- and (5 R)-3-methyl derivatives, two diastereoisomeric adducts were obtained in good yield and stereoselectivity, whereas reaction with the (5 S)- and (5 R)-3-ethoxycarbonyl derivatives led to a complex mixture of products. Subsequent controlled hydrolysis of the pyrazine ring led to β-(3-methyl-4,5-dihydro-isoxazol-5-yl)- l-threonines methyl ester together with the corresponding ( R)-valine dipeptides.

Determination of Conformational Preferences of Dipeptides Using Vibrational Spectroscopy

The NMR coupling constants ((3)J(H(N), H(alpha))) of dipeptides indicate that the backbone conformational preferences vary strikingly among dipeptides. These preferences are similar to those of residues in small peptides, denatured proteins, and the coil regions of native proteins. Detailed characterization of the conformational preferences of dipeptides is therefore of fundamental importance for understanding protein structure and folding. Here, we studied the conformational preferences of 13 dipeptides using infrared and Raman spectroscopy. The main advantage of vibrational spectroscopy over NMR spectroscopy is in its much shorter time scale, which enables the determination of the conformational preferences of short-lived states. Accuracy of structure determination using vibrational spectroscopy depends critically on identification of the vibrational parameters that are sensitive to changes in conformation. We show that the frequencies of the amide I band and the A12 ratio of the amide I components of dipeptides correlate with the (3)J(H(N), H(alpha)). These two infrared vibrational parameters are thus analogous to (3)J(H(N), H(alpha)), indicators for the preference for the dihedral angle phi. We also show that the intensities of the components of the amide III bands in infrared spectra and the intensities of the skeletal vibrations in Raman spectra are indicators of populations of the P(II), beta, and alpha(R) conformations. The results show that alanine dipeptide adopts predominantly a PII conformation. The population of the beta conformation increases in valine dipeptides. The populations of the alpha(R) conformation are generally small. These data are in accord with the electrostatic screening model of conformational preferences.

Using quantum mechanics to improve estimates of amino acid side chain rotamer energies

Amino acid side chains adopt a discrete set of favorable conformations typically referred to as rotamers. The relative energies of rotamers partially determine which side chain conformations are more often observed in protein structures and accurate estimates of these energies are important for predicting protein structure and designing new proteins. Protein modelers typically calculate side chain rotamer energies by using molecular mechanics (MM) potentials or by converting rotamer probabilities from the protein database (PDB) into relative free energies. One limitation of the knowledge-based energies is that rotamer preferences observed in the PDB can reflect internal side chain energies as well as longer-range interactions with the rest of the protein. Here, we test an alternative approach for calculating rotamer energies. We use three different quantum mechanics (QM) methods (second order Møller-Plesset (MP2), density functional theory (DFT) energy calculation using the B3LYP functional, and Hartree-Fock) to calculate the energy of amino acid rotamers in a dipeptide model system, and then use these pre-calculated values in side chain placement simulations. Energies were calculated for over 36,000 different conformations of leucine, isoleucine, and valine dipeptides with backbone torsion angles from the helical and strand regions of the Ramachandran plot. In a subset of cases these energies differ significantly from those calculated with standard molecular mechanics potentials or those derived from PDB statistics. We find that in these cases the energies from the QM methods result in more accurate placement of amino acid side chains in structure prediction tests.

Theoretical Karplus relationships for vicinal coupling constants around χ1 in Valine

Karplus coefficients for χ1-related vicinal coupling constants in Valine dipeptide model, obtained from DFT calculations are reported. The computed coefficients agree with available experimental data, excepting C 1 coefficient that is obtained with negative sign. This apparently anomalous coefficient sign is analyzed within NBO methodology. From this analysis a relationship between the hyperconjugation of the bonding orbitals σ(C–C) and σ(C–H) of the coupling pathway with the vicinal coupling constants is obtained.

Substrate specificity of a metalloprotease of the pappalysin family revealed by an inhibitor and a product complex

Human pappalysin-1 is a multi-domain metalloprotease engaged in the homeostasis of insulin-like growth factors and the founding member of the pappalysin family within the metzincin clan of metalloproteases. We have recently identified an archaeal relative, ulilysin, encompassing only the protease domain. It is a 262-residue active protease with a novel 3D structure with two subdomains separated by an active-site cleft. Despite negligible overall sequence similarity, noticeable similarity is found with other metzincin prototypes, adamalysins/ADAMs and matrix metalloproteinases. Ulilysin has been crystallised in a product complex with an arginine–valine dipeptide occupying the active-site S 1 ′ and S 2 ′ positions and in a complex with the broad-spectrum hydroxamic acid-based metalloprotease inhibitor, batimastat. This molecule inhibits mature ulilysin with an IC 50 value of 61 μM under the conditions assayed. The binding of batimastat to ulilysin evokes binding to vertebrate matrix metalloproteases but is much weaker. These data give insight into substrate specificity and mechanism of action and inhibition of the novel pappalysin family.

Exploring dynamic pathways by action-derived molecular dynamics

Action-derived molecular dynamics for the simulation of rare event and slow mode systems is reviewed. Theoretical background, implementation details, and comparison with other methods are presented. Numerical examples demonstrated include the structural formation and transformation of carbon fullerenes, and molecular reconfiguration of alanine dipeptide and valine dipeptide. It is shown that the action-derived molecular dynamics is efficient to explore the dynamic pathways of various chemical reactions.

Evolution of conformational changes in the dynamics of small biological molecules: a hybrid MD/RRK approach

The dynamics of long timescale evolution of conformational changes in small biological molecules is described by a hybrid molecular dynamics/RRK algorithm. The approach employs classical trajectories for transitions between adjacent structures separated by a low barrier, and the classical statistical RRK approximation when the barrier involved is high. In determining the long-time dynamics from an initial structure to a final structure of interest, an algorithm is introduced for determining the most efficient pathways (sequence of the intermediate conformers). This method uses the Dijkstra algorithm for finding optimal paths on networks. Three applications of the method using an AMBER force field are presented: a detailed study of conformational transitions in a blocked valine dipeptide; a multiple reaction path study of the blocked valine tripeptide; and the evolution in time from the beta hairpin to alpha helix structure of a blocked alanine hexapeptide. Advantages and limitations of the method are discussed in light of the results.

Atomically Detailed Simulations of Helix Formation with the Stochastic Difference Equation

An algorithm is described to compute approximate classical trajectories as a boundary value problem with an integration step in the arc length. High-frequency motions are filtered out when a large integration step is used, maintaining the stability of the algorithm. At the limit of high filtering (large steps), but still offering an accurate description of the continuous path, the trajectory approaches the steepest descent path (SDP). The steepest descent path is widely used as a reaction coordinate in chemical systems. At intermediate step sizes, some inertial motions remain, interpolating between reaction coordinates and exact classical trajectories. Numerical studies of spatial and energetic properties of meta-trajectories are carried out. Two systems are considered here: valine dipeptide and the folding of a small helical protein. Although thermodynamic properties of meta-trajectories are affected by the filtering, the ordering of events remains similar for substantial differences in trajectory resolution.

Synthesis of a conformationally constrained threonine–valine dipeptide mimetic: design of a potential inhibitor of plasminogen activator inhibitor-1

The stereoselective synthesis of a conformationally restricted threonine–valine dipeptide mimetic and its incorporation into a tetrapeptide is described.

A Computational Study of Partially Modified Retro-Inverso Valine Dipeptides: Effect of the Side Chain on the Conformational Preferences of Malonyl and gem-Diamino Residues

A high-level study of the partially modified retro-inverso compounds derived from valine dipeptide, i.e., CH3NHCOCHRCONHCH3 and CH3CONHCHRNHCOCH3 where R = −CH(CH3)2, is presented. Minimum energy conformations were obtained at the HF/6-31G(d) and MP2/6-31G(d) levels from a systematic conformational analysis. The effects of electron correlation and basis set on relative energies were investigated by performing single point calculations at the HF/6-311G(d,p) and MP2/6-311G(d,p) levels on both HF/6-31G(d) and MP2/6-31G(d) geometries. Furthermore, the influence of polar solvents, i.e., water and methanol, on the conformational preferences of the two compounds was determined using the polarizable continuum model. A comparison with results previously obtained for other partially modified retro-inverso dipeptides promoted an understanding of how the side chain affects the conformational preferences of the malonyl and gem-diamino residues.

Multiconfiguration thermodynamic integration

A modified thermodynamic integration technique is presented to obtain free energy differences from molecular dynamics simulations. In this multiconfiguration thermodynamic integration technique, the commonly employed single configuration (slow growth) approximation is not made. It is shown, by analysis of the sources of error, how the multiconfiguration variant of thermodynamic integration allows for a soundly based assessment of the statistical error in the evaluated free energy difference. Since ensembles of configurations are generated for each integration step, a statistical error can be evaluated for each integration step. By generating ensembles of different lengths, the statistical error can be equally distributed over the integration. This eliminates the difficult problem in single configuration thermodynamic integrations of determining the best rate of change of the Hamiltonian, which is usually based on equally distributing the free energy change. At the same time, this procedure leads to a more efficient use of computer time by providing the possibility of added accuracy from separate calculations of the same Hamiltonian change. The technique is applied to a simple but illustrative model system consisting of a monatomic solute in aqueous solution. In a second example, a combination of multiconfiguration thermodynamic integration and thermodynamic perturbation is used to obtain the potentials of mean force for rotation of the sidechain dihedral angles for valine and threonine dipeptides with restrained backbones in aqueous solution.

Reaction of N-terminal valine dipeptides with two ninhydrin derivatives

Reaction of <i>N</i>-terminal valine dipeptides with two ninhydrin derivatives

Conformation equilibria of valine studies by dynamics simulation

The conformational probability distribution of a valine residue in the valine dipeptide and of the valine side chain in an alpha-helix, as well as the change in helix stability for replacing alanine with valine, has been calculated by molecular dynamics simulations of explicitly hydrated systems: dipeptide, tetrapeptide and 10-, 14- and 18-residue oligoalanine helices. All computed free-energy differences are means from at least eight separate slow-growth simulations, four in each direction and are reported with their root-mean-square deviations. Different values for the change in free energy of folding (delta delta G degrees) have been calculated with the use of forcefields having an all-atom and a central-atom representation of methyl groups, etc. The value obtained with the all-atom forcefield agrees well with new experimental values (3 kJ/mol = 0.7 kcal/mol). Furthermore, the most stable valine side-chain rotamer in the helix is different for these two representations. The most stable rotamer for the all atom conformation is the same one that predominates for valines in alpha-helices in proteins of known conformation. The lower conformational freedom of the valine side chain in the helix contributes 1 kJ/mol to the difference in stability computed with the all-atom potential; unfavorable interactions of the side chain with helix, even in the most stable conformation, further increase delta delta G degrees.

Calculation of the potential of mean force using molecular dynamics with linear constraints: An application to a conformational transition in a solvated dipeptide

An algorithm is proposed for the calculation of mean force potentials using molecular dynamics with linear constraints. The new algorithm is based on free energy perturbation and is especially useful when the analytical form of the reaction coordinate is not known (e.g., for a numerically evaluated steepest descent path). It employs only Cartesian coordinates which makes it easy to use for a variety of systems. In particular, it is useful when the reaction coordinate cannot be represented by a single local coordinate or by a combination of a small number of local (internal) coordinates. The linear constraints are solved explicitly and the computational effort required is similar to that of dynamics with no constraints. The potential of mean force for a conformational transition of a solvated valine dipeptide is calculated. In aqueous solution the barriers for the conformational transitions are reduced with respect to the barriers in vacuo, the helix configuration becomes stabilized.