Helix formation in a pentapeptide: experiment and force-field dependent dynamics

We used a combined approach of experiment and simulation to determine the helical population and folding pathway of a small helix forming blocked pentapeptide, Ac-(Ala)(5)-NH(2). Experimental structural characterization of this blocked peptide was carried out with far UV circular dichroism spectroscopy, FTIR, and NMR measurements. These measurements confirm the presence of the α-helical state in a buffer solution. Direct molecular dynamics and replica-exchange simulations of the pentapeptide were performed using several popular force fields with explicit solvent. The simulations yielded statistically reliable estimates of helix populations, melting curves, folding, and nucleation times. The distributions of conformer populations are used to measure folding cooperativity. Finally, a statistical analysis of the sample of helix-coil transition paths was performed. The details of the calculated helix populations, folding kinetics and pathways vary with the employed force field. Interestingly, the helix populations, folding, and unfolding times obtained from most of the studied force fields are in qualitative agreement with each other and with available experimental data, with the deviations corresponding to several kcal/mol in energy at 300 K. Most of the force fields also predict qualitatively similar transition paths, with unfolding initiated at the C-terminus. Accuracy of potential energy parameters, rather than conformational sampling may be the limiting factor in current molecular simulations.     

A Synergistic Effect of Select Organotin Compounds and Ionic Surfactants on Liposome Membranes

Organometallic compounds and surfactants constitute a potential threat to the environment. For that reason we have embarked on a study of their joint action on membranes. Model lecithin liposome membranes were modified with the cationic surfactant trimethyldodecylammonium bromide or the anionic surfactant sodium dodecylsulfonate, and the effect of tripropyltin chloride on the process of calcium (Ca²⁺) and praseodymium (Pr³⁺) desorption from the liposome membrane was studied. Kinetic constants for the process of Ca²⁺ ion desorption from lecithin liposome membranes were determined using the radiotracer method. The percentage of Pr³⁺ ion desorption from liposome membranes was measured by the ¹H NMR method. Trimethyltin, triethyltin and tripropyltin alone caused increased Ca²⁺ and Pr³⁺ desorption from liposome membranes with increasing concentration of the compounds and alkyl chain length. For both the processes studied, a cationic surfactant brought about a lower effectiveness of tripropyltin and an anionic surfactant resulted in a higher effectiveness. The effect observed can be explained by changes in the surface charge of the membrane, induced by the surfactant modifiers and by the concomitant change in the partition coefficient of the organotin. The results obtained indicate a protective or harmful joint action of the surfactants used with tripropyltin on membranes. © 1997 John Wiley & Sons, Ltd.     

Transport properties of CO2-expanded acetonitrile from molecular dynamics simulations

Carbon-dioxide-expanded liquids, which are mixtures of organic liquids and compressed CO2, are novel media used in chemical processing. The authors present a molecular simulation study of the transport properties of liquid mixtures formed by acetonitrile and carbon dioxide, in which the CO2 mole fraction is adjusted by changing the pressure, at a constant temperature of 298 K. They report values of translational diffusion coefficients, rotational correlation times, and shear viscosities of the liquids as function of CO2 mole fraction. The simulation results are in good agreement with the available experimental data for the pure components and provide interesting insights into the largely unknown properties of the mixtures, which are being recognized as important novel materials in chemical operations. We find that the calculated quantities exhibit smooth variation with composition that may be represented by simple model equations. The translational and rotational diffusion rates increase with CO2 mole fraction for both the acetonitrile and carbon dioxide components. The shear viscosity decreases with increasing amount of CO2, varying smoothly between the values of pure acetonitrile and pure carbon dioxide. Our results show that adjusting the amount of CO2 in the mixture allows the variation of transport rates by a factor of 3-4 and liquid viscosity by a factor of 8. Thus, the physical properties of the mixture may be tailored to the desired range by changes in the operating conditions of temperature and pressure.     

Rheo-NMR in food science—Recent opportunities

For over 25 years, nuclear magnetic resonance (NMR) and magnetic resonance imaging (MRI) techniques have been used to study materials under mechanical deformation. Collectively, these methods are referred to as Rheo-NMR. In many cases, it provides spatially and temporally resolved maps of NMR spectra, intrinsic NMR parameters (such as relaxation times), or motion (such as diffusion or flow). Therefore, Rheo-NMR is complementary to conventional rheological measurements. This review will briefly summarize current capabilities and limitations of Rheo-NMR in the context of material science and food science in particular. It will report on recent advances such as the incorporation of torque sensors or the implementation of large amplitude oscillatory shear and point out future opportunities for Rheo-NMR in food science.     

Phase equilibria in carbon dioxide expanded solvents: Experiments and molecular simulations

We present complementary molecular simulations and experimental results of phase equilibria for carbon dioxide expanded acetonitrile, methanol, ethanol, acetone, acetic acid, toluene, and 1-octene. The volume expansion measurements were done using a high-pressure Jerguson view cell. Molecular simulations were performed using the Gibbs ensemble Monte Carlo method. Calculations in the canonical ensemble (NVT) were performed to determine the coexistence curve of the pure solvent systems. Binary mixtures were simulated in the isobaric-isothermal distribution (NPT). Predictions of vapor-liquid equilibria of the pure components agree well with experimental data. The simulations accurately reproduced experimental data on saturated liquid and vapor densities for carbon dioxide, methanol, ethanol, acetone, acetic acid, toluene, and 1-octene. In all carbon dioxide expanded liquids (CXL's) studied, the molecular simulation results for the volume expansion of these binary mixtures were found to be as good as, and in many cases superior to, predictions based on the Peng-Robinson equation of state, demonstrating the utility of molecular simulation in the prediction of CXL phase equilibria.     

One- and multidimensional conformational free energy simulations

A new thermodynamic integration approach to conformational free energy simulations is presented. The method is applicable both to one-dimensional cases (reaction coordinates) and multidimensional situations (free energy surfaces). Analysis of the properties of the thermodynamic integration algorithm is used to formulate methods of calculating multidimensional free energy gradients. The method is applied to calculate the free energy profile for rotation around the central C—C bond of n-butane in the gas and liquid phase and to generate maps of the 18-dimensional free energy gradient with respect to all nine ϕ and nine ψ dihedrals of the decaalanine and deca-α-methylalanine peptides in vacuum. For n-butane essentially no change in the gauche–trans equilibrium between the gas and liquid is predicted within the CHARMM explicit hydrogen model, with the thermodynamic integration, thermodynamic perturbation, and direct simulation methods yielding free energy profiles that are identical within errors. For the decapeptides the right-handed helical region of conformational space is investigated. For decaalanine a minimum on the free energy surface is found in the vicinity of (ϕ, ψ) = (-64.5°, -42.5°) in the α-helix region; no minimum exists for 3₁₀-helix-type conformers. For deca-α-methylalanine free energy minima corresponding to both the α-helix at ( - 55.5°, - 51.5°) and the 3₁₀-helix at ( - 54°, - 29°) are found; the α-helix state is favored by about 4 kcal/mol and the barrier for the concerted 3₁₀-helix → α-helix transition is about 3 kcal/mol. The α-methylation also considerably increases the rigidity of the α-helix with respect to deformations. The computational efficiency, ease of generalization to calculations of multidimensional gradients, and analytical capability due to component analysis of free energy differences make the method a novel, powerful tool to improve the basic understanding of conformational equilibria of flexible molecules in condensed phases. A related scheme for energy minimization in the presence of holonomic constraints is also presented, allowing generation of adiabatic energy surfaces in constrained systems. © 1996 by John Wiley & Sons, Inc.     

Conformational free energy surface of the linear DPDPE peptide: cost of pre-organization for disulfide bond formation

We have calculated the free energy differences between four conformers of the linear form of the opioid pentapeptide DPDPE in aqueous solution. The conformers are Cyc, representing the structure adopted by the linear peptide prior to disulfide bond formation, β _C and β _E , two slightly different β-turns previously identified in unconstrained molecular dynamics simulations, and Ext, an extended structure. Our simulations indicate that β _E is the most stable of the studied conformers of linear DPDPE in aqueous solution, with β _C , Cyc and Ext having free energies higher by 2.3, 6.3, and 28.2 kcal/mol, respectively. The free energy differences of 4.0 kcal/mol between β _C and Cyc, and 6.3 kcal/mol between β _E and Cyc, reflect the cost of pre-organizing the linear peptide into a conformation conducive for disulfide bond formation. Such a conformational change is a pre-requisite for the chemical reaction of S–S bond formation to proceed. The relatively low population of the cyclic-like structure agrees qualitatively with observed lower potency and different receptor specificity of the linear form relative to the cyclic peptide, and with previous unconstrained simulation results. Free energy component analysis indicates that the moderate stability difference of 4.0–6.3 kcal/mol between the β-turns and the cyclic-like structure results from cancellation of two large opposing effects. In accord with intuition, the relaxed β-turns have conformational strain 43–45 kcal/mol lower than the Cyc structure. However, the cyclic-like conformer interacts with water about 39 kcal/mol strongly than the open β-turns. Our simulations are the first application of the recently developed multidimensional conformational free energy thermodynamic integration (CFTI) protocol to a solvated system, with fast convergence of the free energy obtained by fixing all flexible dihedrals. Additionally, the availability of the CFTI multidimensional free energy gradient leads to a new decomposition scheme, giving the contribution of each fixed dihedral to the overall free energy change and providing additional insight into the microscopic mechanisms of the studied processes. Received: 20 April 1998 / Accepted: 9 September 1998 / Published online: 7 December 1998     

Autoassociates and tautomerism of 2-oxo-5-halogenopyrimidines: theoretical and experimental investigations

Theoretical calculations (on a semi-empirical level) of energy and geometry of the autoassociates of two tautomeric forms of 2-oxo-5X-pyrimidines (X = H, Cl, Br) are presented. On the basis of the calculated energies of autoassociates it is possible to explain the enol—keto tautomeric transition between the gas phase and condensed phases. We propose a double-proton transfer reaction as a possible mechanism for the tautomeric transition.

Infrared absorption spectra of 2-oxo-5X-pyrimidines in the v(NH …) and v(C=O) regions in solid phases and in low-temperature argon matrices are also presented and discussed. Comparison of IR spectra and results of the theoretical calculations with known crystallographic structures of 2-oxo-5X-pyrimidines (X = H, F, Cl) lead to the conclusion that the crystal structure of the 5-bromo derivative should be similar to that of the 5-chloro derivative.