Effect of mutations involving charged residues on the stability of staphylococcal nuclease: a continuum electrostatics study

A continuum electrostatics model is used to calculate the relative stabilities of 117 mutants of staphylococcal nuclease (SNase) involving the mutation of a charged residue to an uncharged residue. The calculations are based on the crystallographic structure of the wild‐type protein and attempt to take implicitly into account the effect of the mutations in the denatured state by assuming a linear relationship between the free energy changes caused by the mutation in the native and denatured states. A good correlation (linear correlation coefficient of ∼0.8) is found with published experimental relative stabilities of these mutants. The results suggest that in the case of SNase (i) charged residues contribute to the stability of the native state mainly through electrostatic interactions, and (ii) native‐like electrostatic interactions may persist in the denatured state. The continuum electrostatics method is only moderately sensitive to model parameters and leads to quasi‐predictive results for the relative mutant stabilities (error of 2-3 kJ mol-1 or of the order of kBT), except for mutants in which a charged residue is mutated to glycin

Optimized Periodic Coulomb Potential in Two Dimension

The 1/r Coulomb potential is calculated for a two dimensional system with periodic boundary conditions. Using polynomial splines in real space and a summation in reciprocal space we obtain numerically optimized potentials which allow us efficient calculations of any periodic (long-ranged) potential up to high precision. We discuss the parameter space of the optimized potential for the periodic Coulomb potential. Compared to the analytic Ewald potential, the optimized potentials can reach higher precisions by up to several orders of magnitude. We explicitly give simple expressions for fast calculations of the periodic Coulomb potential where the summation in reciprocal space is reduced to a few terms

Residual structure in a peptide fragment of the outer membrane protein X under denaturing conditions: a molecular dynamics study

The Escherichia coli outer membrane protein X (OmpX) contains two polypeptide segments that present nonrandom residual structure in 8M aqueous urea, whereas the remainder of the protein is in a flexibly disordered conformation (Tafer et al. in Biochemistry 43:860-869, 2004). In the present study, the results of two long-timescale (0.4μs) unrestrained explicit-solvent molecular dynamics (MD) simulations of a tetradecapeptide representative of one of these two segments in 8M aqueous urea are reported and analyzed. The two simulations were initiated either from the conformation of the corresponding segment in an NMR model structure of the unfolded protein or from an entirely extended configuration. The sampled conformational ensembles agree qualitatively with the experimentally observed NOEs, but not quantitatively, suggesting that a number of relevant configurations were not visited on the 2×0.4μs timescale. Major conformational transitions occur on the 0.1μs timescale, and the ensembles corresponding to the two independent simulations overlap only to a limited extent. However, both simulations show in multiple events the reversible formation and disruption of α-helical secondary structure (characteristic of the urea-denatured state) and β-turn secondary structure (characteristic of the native state). Events of helix formation are correlated with the appearance of hydrogen bonds between two side chains (Asp75-Ser78) and of a persistent hydrophobic contact (Trp76-Tyr80). They also evidence a peculiar helix stabilization and N-terminal capping role for a negatively charged residue (Asp75). These features are in good qualitative agreement with the NMR model for the structured state of the corresponding segment in the urea-denatured protein. The analysis of the simulations provides a detailed picture of the structural and dynamic features of the considered peptide at atomic resolution that is of high relevance in the understanding of the OmpX folding proces

Comparison of Dissipative Particle Dynamics and Langevin thermostats for out-of-equilibrium simulations of polymeric systems

In this work we compare and characterize the behavior of Langevin and Dissipative Particle Dynamics (DPD) thermostats in a broad range of non-equilibrium simulations of polymeric systems. Polymer brushes in relative sliding motion, polymeric liquids in Poiseuille and Couette flows, and brush-melt interfaces are used as model systems to analyze the efficiency and limitations of different Langevin and DPD thermostat implementations. Widely used coarse-grained bead-spring models under good and poor solvent conditions are employed to assess the effects of the thermostats. We considered equilibrium, transient, and steady state examples for testing the ability of the thermostats to maintain constant temperature and to reproduce the underlying physical phenomena in non-equilibrium situations. The common practice of switching-off the Langevin thermostat in the flow direction is also critically revisited. The efficiency of different weight functions for the DPD thermostat is quantitatively analyzed as a function of the solvent quality and the non-equilibrium situation.Comment: 12 pages, introduction improved, references added, to appear in Phys. Rev.

The role of the nature of the noise in the thermal conductance of mechanical systems

Focussing on a paradigmatic small system consisting of two coupled damped oscillators, we survey the role of the L\'evy-It\^o nature of the noise in the thermal conductance. For white noises, we prove that the L\'evy-It\^o composition (Lebesgue measure) of the noise is irrelevant for the thermal conductance of a non-equilibrium linearly coupled chain, which signals the independence between mechanical and thermodynamical properties. On the other hand, for the non-linearly coupled case, the two types of properties mix and the explicit definition of the noise plays a central role.Comment: 9 pages, 2 figures. To be published in Physical Review

Intramolecular hydrogen-bonding in aqueous carbohydrates as a cause or consequence of conformational preferences: a molecular dynamics study of cellobiose stereoisomers

It is often assumed that intramolecular hydrogen-bonding (H-bonding) exerts a significant influence on the conformational properties of aqueous (bio-)polymers. To discuss this statement, one should, however, distinguish between solvent-exposed and buried H-bonds, and between their respective roles in promoting stability (i.e., as a driving force) and specificity (for which the term steering force is introduced here). In this study, the role of solvent-exposed H-bonding in carbohydrates as a driving or steering force is probed using explicit-solvent molecular dynamics simulations with local elevation umbrella sampling in the simple context of cellobiose stereoisomers. More specifically, four β(1→4)-linked d-aldohexopyranose disaccharides are considered, which present a different stereochemisty of the potentially H-bonding groups neighboring the glycosidic linkage. Although the epimerization may largely alter the intramolecular trans-glycosidic H-bonding pattern, it is found to have only very limited influence on the Ramachandran free-energy map of the disaccharide, a loss of intramolecular H-bonding being merely compensated for by an enhancement of the interaction with the solvent molecules. This finding suggests that solvent-exposed trans-glycosidic H-bonding (and in particular the $$\hbox{HO}_3^{\prime}$$ →O5 H-bond) is not the cause of the 21-helical secondary structure characteristic of cellooligosaccharides, but rather the opportunistic consequence of a sterically and stereoelectronically dictated conformational preference. In other words, for these compounds, solvent-exposed H-bonding appears to represent a minor (possibly adverse) conformational driving as well as steering forc

Thiol density dependent classical potential for methyl-thiol on a Au(111) surface

A new classical potential for methyl-thiol on a Au(111) surface has been developed using density functional theory electronic structure calculations. Energy surfaces between methyl-thiol and a gold surface were investigated in terms of symmetry sites and thiol density. Geometrical optimization was employed over all the configurations while minimum energy and thiol height were determined. Finally, a new interatomic potential has been generated as a function of thiol density, and applications to coarse-grained simulations are presented

RKKY interaction in one-dimensional flat band lattices

We study the Ruderman-Kittel-Kasuya-Yosida (RKKY) interaction between two classical magnetic impurities in one-dimensional lattice models with flat bands. As two representative examples, we pick the stub lattice and the diamond lattice at half filling. We first calculate the exact RKKY interaction numerically and then compare our data to results obtained via different analytical techniques. In both our examples, we find that the RKKY interaction exhibits peculiar features that can directly be traced back to the presence of a flat band. Importantly, these features are not captured by the conventional RKKY approximation based on non-degenerate perturbation theory. Instead, we find that degenerate perturbation theory correctly reproduces our exact results if there is an energy gap between the flat and the dispersive bands, while a non-perturbative approach becomes necessary in the absence of a gap

Effect of the cosolutes trehalose and methanol on the equilibrium and phase-transition properties of glycerol-monopalmitate lipid bilayers investigated using molecular dynamics simulations

The influence of the cosolutes trehalose and methanol on the structural, dynamic and thermodynamic properties of a glycerol-1-monopalmitate (GMP) bilayer and on its main transition temperature $$T_m$$ T m is investigated using atomistic molecular dynamics simulations (600 ns) of a GMP bilayer patch (2×8×8 lipids) at different temperatures in the range of 302 to 338 K and considering three different cosolute concentrations. Depending on the environment and temperature, these simulations present no or a single GL $$\rightarrow$$ → LC, LC $$\rightarrow$$ → GL or LC $$\rightarrow$$ → ID transition, where LC, GL and ID are the liquid crystal, gel and interdigitated phases, respectively. The trehalose molecules form a coating layer at the bilayer surface, promote the hydrogen-bonded bridging of the lipid headgroups, preserve the interaction of the headgroups with trapped water and induce a slight lateral expansion of the bilayer in the LC phase, observations that may have implications for the phenomenon of anhydrobiosis. However, this cosolute does not affect $$T_m$$ T m and its dependence on hydration in the concentration range considered. On the other hand, methanol molecules intercalate between the lipid headgroups, promote a lateral expansion of the bilayer in the LC phase and induce a concentration dependent decrease of $$T_m$$ T m , observations that may have implications for the phenomenon of anesthesia. The occurrence of an ID phase in the presence of this cosolute may be viewed as an extreme consequence of lateral expansion. The analysis of the simulations also suggests the existence of two basic conservation principles: (1) the hydrogen-bond saturation principle rests on the observation that for all species present in the different systems, the total numbers of hydrogen-bonds per molecule is essentially constant, the only factor of variability being their distribution among different partners; (2) the densest packing principle rests on the observation that the effective volume per methylene group in the interior of the bilayer is only weakly sensitive to the environment, with values comparable to those for liquid (LC) and solid (ID) alkanes, or intermediate (GL)