Breakdown of Langmuir Adsorption Isotherm in Small Closed Systems.

For more than a century, monolayer adsorptions in which adsorbate molecules and adsorbing sites behave ideally have been successfully described by Langmuir's adsorption isotherm. For example, the amount of adsorbed material, as a function of concentration of the material which is not adsorbed, obeys Langmuir's equation. In this paper, we argue that this relation is valid only for macroscopic systems. However, when particle numbers of adsorbate molecules and/or adsorbing sites are small, Langmuir's model fails to describe the chemical equilibrium of the system. This is because the kinetics of forming, or the probability of observing, occupied sites arises from two-body interactions, and as such, ought to include cross-correlations between particle numbers of the adsorbate and adsorbing sites. The effect of these correlations, as reflected by deviations in predicting composition when correlations are ignored, increases with decreasing particle numbers and becomes substantial when only few adsorbate molecules, or adsorbing sites, are present in the system. In addition, any change that augments the fraction of occupied sites at equilibrium (e.g., smaller volume, lower temperature, or stronger adsorption energy) further increases the discrepancy between observed properties of small systems and those predicted by Langmuir's theory. In contrast, for large systems, these cross-correlations become negligible, and therefore when expressing properties involving two-body processes, it is possible to consider independently the concentration of each component. By applying statistical mechanics concepts, we derive a general expression of the equilibrium constant for adsorption. It is also demonstrated that in ensembles in which total numbers of particles are fixed, the magnitudes of fluctuations in particle numbers alone can predict the average chemical composition of the system. Moreover, an alternative adsorption equation, predicting the average fraction of occupied sites from the value of the equilibrium constant, is proposed. All derived relations were tested against results obtained by Monte Carlo simulations.

Multimerizations, Aggregation, and Transfer Reactions of Small Numbers of Molecules.

Chemical equilibria of multimerizations in systems with small numbers of particles exhibit a behavior seemingly at odds with that observed macroscopically. In this paper, we apply the recently proposed expression of equilibrium constant for binding, which includes cross-correlations in reactants' concentrations, to write an equilibrium constant for the formation of clusters larger than two (e.g., trimer, tetramer, and pentamer) as series of two-body reactions. Results obtained by molecular dynamics simulations demonstrate that the value of this expression is constant for all concentrations and system sizes, as well as at an onset of a phase transition to an aggregated state, where densities in the system change discontinuously. In contrast, the value of the commonly utilized expression of equilibrium constant, which ignores correlations, is not constant and its variations can reach few orders of magnitude. Considering different paths for the same multimer formation, with elementary reactions of any order, yields different expressions for the equilibrium constant, yet, with exactly the same value. This is also true for routes with essentially zero probability to occur. Existence of different expressions for the same equilibrium constant imposes equalities between averages of correlated, along with uncorrelated, concentrations of participating species. Moreover, a relation between an average particle number and relative fluctuations derived for two-body reactions is found to be obeyed here as well despite couplings to additional equilibrium reactions in the system. Analyses of transfer reactions, where association and dissociation events take place on both sides of the chemical equation, further indicate the necessity to include cross-correlations in the expression of the equilibrium constant. However, in this case, the magnitudes of discrepancies of the uncorrelated expression are smaller, likely because of partial cancellation of correlations, which exist on both the reactant and product sides.

Statistical mechanics of dimerizations and its consequences for small systems.

Utilizing a statistical mechanics framework, we derive the expression of the equilibrium constant for dimerization reactions. An important feature arising from the derivation is the necessity to include two-body correlations between monomer's number of particles, reminiscent to those recently found crucial for binding reactions. However in (homo-) dimerizations, particles of the same type associate, and therefore, self-correlations are excluded. As a result, the mathematical form of the equilibrium constant differs from the well-known expression given in textbooks. For systems with large number of particles the discrepancy is negligible, whereas, for finite systems it is significant. Rationalized by collision probability between monomers, the bimolecular rate for dimer formation is proportional to concentration the same way correlations are accounted for. That is average of squared, and not square of averaged, monomer concentration should be considered in such a way that inconceivable collisions between a tagged particle with itself are excluded. Another consequence emerging from these two-body correlations, is an inhomogeneous function behavior of system's properties upon scaling-down the system to a regime smaller than the thermodynamic limit. Thus, averages of properties observed at small systems are different than those observed at macroscopic systems. All predictions are verified by Monte Carlo and molecular dynamics simulations.

Binding reactions at finite systems.

A perpetual yearn exists among computational scientists to scale down the size of physical systems, a desire shared as well with experimentalists able to track single molecules. A question then arises whether averages observed at small systems are the same as those observed at large or macroscopic systems. Utilizing statistical-mechanics formulations in ensembles in which the total numbers of particles are fixed, we demonstrate that properties of binding reactions are not homogeneous functions. This means that averages of intensive parameters, such as the concentration of the bound-state, at finite systems are different than those at large systems. The discrepancy increases with decreasing temperature, volume, and to some extent, numbers of particles. As perplexing as it may sound, despite variations in average quantities, extracting the equilibrium constant from systems of different sizes does yield the same value. The reason is that correlations in reactants' concentrations ought to be accounted for in the expression of the equilibrium constant, being negligible at large-scale but significant at small-scale. Similar arguments pertain to the calculations of the reaction rate constants, more specifically, the bimolecular rate of the forward reaction is related to the average of the product (and not to the product of the averages) of the reactants' concentrations. Furthermore, we derive relations aiming to predict the composition only from the equilibrium constant and the system's size. All predictions are validated by Monte-Carlo and molecular dynamics simulations. An important consequence of these findings is that the expression of the equilibrium constant at finite systems is not dictated solely by the chemical equation of the reaction but requires knowledge of the elementary processes involved.

Adsorption-induced clustering of CO2 on graphene.

Utilization of graphene-based materials for selective carbon dioxide capture has been demonstrated recently as a promising technological approach. In this study we report results from density functional theory calculations and molecular dynamics simulations on the adsorption of CO2, N2, and CH4 gases on a graphene sheet. We calculate adsorption isotherms of ternary and binary mixtures of these gases and reproduce the larger selectivity of CO2 to graphene relative to the other two gases. Furthermore it is shown that the confinement to two-dimensions, associated with adsorbing the CO2 gas molecules on the plane of graphene, increases their propensity to form clusters on the surface. Above a critical surface coverage (or partial pressure) of the gas, these CO2-CO2 interactions augment the effective adsorption energy to graphene, and, in part, contribute to the high selectivity of carbon dioxide with respect to nitrogen and methane. The origin of the attractive interaction between the CO2 molecules adsorbed on the surface is of electric quadrupole-quadrupole nature, in which the positively-charged carbon of one molecule interacts with the negatively-charged oxygen of another molecule. The energy of attraction of forming a CO2 dimer is predicted to be around 5-6 kJ mol-1, much higher than the corresponding values calculated for N2 and CH4. We also evaluated the adsorption energies of these gases to a graphene sheet and found that the attractions obtained using the classical force-fields might be over-exaggerated. Nevertheless, even when the magnitudes of these (classical force-field) graphene-gas interactions are scaled-down sufficiently, the tendency of CO2 molecules to cluster on the surface is still observed.

Reduced Graphene Oxide/Polymer Monolithic Materials for Selective CO2 Capture.

Polymer composite materials with hierarchical porous structure have been advancing in many different application fields due to excellent physico-chemical properties. However, their synthesis continues to be a highly energy-demanding and environmentally unfriendly process. This work reports a unique water based synthesis of monolithic 3D reduced graphene oxide (rGO) composite structures reinforced with poly(methyl methacrylate) polymer nanoparticles functionalized with epoxy functional groups. The method is based on reduction-induced self-assembly process performed at mild conditions. The textural properties and the surface chemistry of the monoliths were varied by changing the reaction conditions and quantity of added polymer to the structure. Moreover, the incorporation of the polymer into the structures improves the solvent resistance of the composites due to the formation of crosslinks between the polymer and the rGO. The monolithic composites were evaluated for selective capture of CO2. A balance between the specific surface area and the level of functionalization was found to be critical for obtaining high CO2 capacity and CO2/N2 selectivity. The polymer quantity affects the textural properties, thus lowering its amount the specific surface area and the amount of functional groups are higher. This affects positively the capacity for CO2 capture, thus, the maximum achieved was in the range 3.56-3.85 mmol/g at 1 atm and 25 °C.

Refinement of the OPLSAA Force-Field for Liquid Alcohols.

We employ the popular all-atom optimized potential for liquid simulations, OPLSAA, force-field to model 17 different alcohols in the liquid state. Using the standard simulation protocol for few hundred nanosecond time periods, we find that 1-octanol, 1-nonanol, and 1-decanol undergo spontaneous transition to a crystalline state at temperatures which are 35-55 K higher than the experimental melting temperatures. Nevertheless, the crystal structures obtained from the simulations are very similar to those determined by X-ray powder diffraction data for several n-alcohols. Although some degree of deviations from the experimental freezing points are to be expected, for 1-nonanol and 1-decanol, the elevation of the freezing temperature warrants special attention because at room temperature, these alcohols are liquids; however, if simulated by the OPLSAA force-field, they will crystallize. This behavior is likely a consequence of exaggerated attractive interactions between the alkane chains of the alcohols. To circumvent this problem, we combined the OPLSAA model with the L-OPLS force-field. We adopted the L-OPLS parameters to model the hydrocarbon tail of the alcohols, whereas the hydroxyl head group remained as in the original OPLSAA force-field. The resulting alcohols stayed in the liquid state at temperatures above their experimental melting points, thus, resolving the enhanced freezing observed with the OPLSAA force-field. In fact, the mixed-model alcohols did not exhibit any spontaneous freezing even at temperatures much lower than the experimental values. However, a series of simulations in which these mixed-OPLSAA alcohols started from a coexistence configuration of the liquid and solid phases resulted in freezing transitions at temperatures 14-25 K lower than the experimental values, confirming the validity of the proposed model. For all of the other alcohols, the mixed model yields results very similar to the OPLSAA force-field and is in good agreement with the experimental data. Thus, for simulating alcohols in the liquid phase, the mixed-OPLSAA model is necessary for large (7 carbons and above) hydrocarbon chains.

Shedding light on the different behavior of ionic and nonionic surfactants in emulsion polymerization: from atomistic simulations to experimental observations.

Although surfactants are known to play a vital role in polymerization reactions carried out in dispersed media, many aspects of their use are poorly understood, perhaps none more so than the vastly different action of ionic and nonionic surfactants in emulsion polymerization. In this work, we combine experimental measurements of emulsion polymerization of styrene with atomistic molecular dynamics simulations to better understand the behavior of surfactants at monomer/polymer-water interfaces. In a batch emulsion polymerization of styrene, the nonionic surfactant Disponil AFX 1080 leads to two nucleation periods, in contrast to the behavior observed for the ionic surfactant SDS. This can be explained by the absorption of the nonionic surfactant into the organic phase at the early stages of the polymerization reaction which is then released as the reaction progresses. Indeed, we find that the partition coefficient of the surfactant between the organic phase and water increases with the amount of monomer in the former, and preferential partitioning is detected to organic phases containing at least 55% styrene. Results from molecular dynamics simulations confirm that spontaneous dissolution of the non-ionic surfactant into a styrene-rich organic phase occurs above a critical concentration of the surfactant adsorbed at the interface. Above this critical concentration, a linear correlation between the amount of surfactant adsorbed at the interface and that absorbed inside the organic phase is observed. To facilitate this absorption into a completely hydrophobic medium, water molecules accompany the intruding surfactants. Similar simulations but with the ionic surfactant instead did not result in any absorption of the surfactant into a neat styrene phase, likely because of its strongly hydrophilic head group. The unusual partitioning behavior of nonionic surfactants explains a number of observable features of emulsion polymerization reactions which use nonionic surfactants and should help with future development of processes for improved control over polymerization.

Adsorption mechanism of an antimicrobial peptide on carbonaceous surfaces: A molecular dynamics study.

Peptides are versatile molecules with applications spanning from biotechnology to nanomedicine. They exhibit a good capability to unbundle carbon nanotubes (CNT) by improving their solubility in water. Furthermore, they are a powerful drug delivery system since they can easily be uptaken by living cells, and their high surface-to-volume ratio facilitates the adsorption of molecules of different natures. Therefore, understanding the interaction mechanism between peptides and CNT is important for designing novel therapeutical agents. In this paper, the mechanisms of the adsorption of antimicrobial peptide Cecropin A-Magainin 2 (CA-MA) on a graphene nanosheet (GNS) and on an ultra-short single-walled CNT are characterized using molecular dynamics simulations. The results show that the peptide coats both GNS and CNT surfaces through preferential contacts with aromatic side chains. The peptide packs compactly on the carbon surfaces where the polar and functionalizable Lys side chains protrude into the bulk solvent. It is shown that the adsorption is strongly correlated to the loss of the peptide helical structure. In the case of the CNT, the outer surface is significantly more accessible for adsorption. Nevertheless when the outer surface is already covered by other peptides, a spontaneous diffusion, via the amidated C-terminus into the interior of the CNT, was observed within 150 ns of simulation time. We found that this spontaneous insertion into the CNT interior can be controlled by the polarity of the entrance rim. For the positively charged CA-MA peptide studied, hydrogenated and fluorinated rims, respectively, hinder and promote the insertion.

Adsorption and desorption behavior of ionic and nonionic surfactants on polymer surfaces.

We report combined experimental and computational studies aiming to elucidate the adsorption properties of ionic and nonionic surfactants on hydrophobic polymer surface such as poly(styrene). To represent these two types of surfactants, we choose sodium dodecyl sulfate and poly(ethylene glycol)-poly(ethylene) block copolymers, both commonly utilized in emulsion polymerization. By applying quartz crystal microbalance with dissipation monitoring we find that the non-ionic surfactants are desorbed from the poly(styrene) surface slower, and at low surfactant concentrations they adsorb with stronger energy, than the ionic surfactant. If fact, from molecular dynamics simulations we obtain that the effective attractive force of these nonionic surfactants to the surface increases with the decrease of their concentration, whereas, the ionic surfactant exhibits mildly the opposite trend. We argue that the difference in this contrasting behavior stems from the physico-chemical properties of the head group. Ionic surfactants characterized by small and strongly hydrophilic head groups form an ordered self-assembled structure at the interface whereas, non-ionic surfactants with long and weakly hydrophilic head groups, which are also characterized by low persistence lengths, generate a disordered layer. Consequently, upon an increase in concentration, the layer formed by the nonionic surfactants prevents the aprotic poly(ethylene glycol) head groups to satisfy all their hydrogen bonds capabilities. As a response, water molecules intrude this surfactant layer and partially compensate for the missing interactions, however, at the expense of their ability to form hydrogen bonds as in bulk. This loss of hydrogen bonds, either of the head groups or of the intruding water molecules, is the reason the nonionic surfactants weaken their effective attraction to the interface with the increase in concentration.

Strings-to-Rings Transition and Antiparallel Dipole Alignment in Two-Dimensional Methanols.

Structural order emerging in the liquid state necessitates a critical degree of anisotropy of the molecules. For example, liquid crystals and Langmuir monolayers require rod- or disc-shaped and long-chain amphiphilic molecules, respectively, to break the isotropic symmetry of liquids. In this Letter we present results from molecular dynamics simulations demonstrating that in two-dimensional liquids, a significantly smaller degree of anisotropy is sufficient to allow structural organization. In fact, the condensed phase of the smallest amphiphilic molecule, methanol, confined between two, or adsorbed on, graphene sheets forms a monolayer characterized by long chains of molecules. Intrachain interactions are dominated by hydrogen bonds, whereas interchain interactions are dispersive. Upon a decrease in density toward a gaslike state, these strings are transformed into rings. The two-dimensional liquid phase of methanol undergoes another transition upon cooling; in this case, the order-disorder transition is characterized by a low-temperature phase in which the hydrogen bond dipoles of neighboring strings adopt an antiparallel orientation.

Role of side-chain interactions on the formation of α-helices in model peptides.

The role played by side-chain interactions on the formation of α-helices is studied using extensive all-atom molecular dynamics simulations of polyalanine-like peptides in explicit TIP4P water. The peptide is described by the OPLS-AA force field except for the Lennard-Jones interaction between Cß-Cß atoms, which is modified systematically. We identify values of the Lennard-Jones parameter that promote α-helix formation. To rationalize these results, potentials of mean force (PMF) between methane-like molecules that mimic side chains in our polyalanine-like peptides are computed. These PMF exhibit a complex distance dependence where global and local minima are separated by an energy barrier. We show that α-helix propensity correlates with values of these PMF at distances corresponding to Cß-Cß of i-i+3 and other nearest neighbors in the α-helix. In particular, the set of Lennard-Jones parameters that promote α-helices is characterized by PMF that exhibit a global minimum at distances corresponding to i-i+3 neighbors in α-helices. Implications of these results are discussed.

Molecular dynamics study of the recognition of dimethylated CpG sites by MBD1 protein.

The cell is able to regulate which genes to express via chemical marks on the DNA and on the histone proteins. In all vertebrates, the modification on the DNA is methylation at position 5 of the two cytosines present in the dinucleotide sequence CpG. The information encoded by these chemical marks on the DNA is processed by a family of protein factors containing a conserved methyl-CpG binding domain (MBD). Essential to their function, the MBD proteins are able to bind DNA containing dimethylated CpG sites, whereas binding to unmethylated sites is not observed. In this paper, we perform molecular dynamics simulations to investigate the mechanism by which the mCpG binding domain of MBD1 is able to bind specifically dimethylated CpG sites. We find that the binding affinity of MBD1 to a DNA containing dimethylated CpG site is stronger by 26.4 kJ/mol relative to binding the same DNA but with an unmethylated CpG site. The contribution of each of the methyl groups to the change in free energy is very similar and additive. Therefore, this binding affinity (to a dimethylated DNA) is halved when considered relative to binding a hemimethylated DNA, a result that is also supported by experimental observations. Despite their equal contributions, the two methyl groups are recognized differently by MBD1. In one case, demethylation induces conformational changes in which the hydrophobic patch formed by the conserved residues Val20, Arg22, and Tyr34 moves away from the (methyl)cytosine, weakening the DNA-protein interactions. This is accompanied by an intrusion of a bulk water into the binding site at the protein-DNA interface. As a consequence, there is a reduction and rearrangements of the protein-DNA hydrogen bonds including a loss of a crucial hydrogen bond between Tyr34 and the (methyl)cytosine. The methylcytosine on the opposite strand is recognized by conformational changes of the surrounding conserved hydrophobic residues, Arg44 and Ser45, in which Arg44 participate in the 5mC-Arg-G triad. More specifically, the hydrogens of the methyl group form weak hydrogen bonds with the guanidino group and backbone carbonyl of the conserved Arg44, interactions that are absent when the cytosine is unmethylated. The results presented in this paper contribute to our knowledge of the different ways the chemical mark on the DNA is recognized by the epigenetic machinery.

Divergence of the long-wavelength collective diffusion coefficient in quasi-one- and quasi-two-dimensional colloidal suspensions.

We report the results of experimental studies of the short-time-long-wavelength behavior of collective particle displacements in quasi-one-dimensional (q1D) and quasi-two-dimensional (q2D) colloid suspensions. Our results are reported via the q → 0 behavior of the hydrodynamic function H(q) that relates the effective collective diffusion coefficient D(e)(q), with the static structure factor S(q) and the self-diffusion coefficient of isolated particles D(0): H(q) ≡ D(e)(q)S(q)/D(0). We find an apparent divergence of H(q) as q → 0 with the form H(q) ∝ q(-γ) (1.7 < γ < 1.9) for both q1D and q2D colloid suspensions. Given that S(q) does not diverge as q → 0 we infer that D(e)(q) does. This behavior is qualitatively different from that of the three-dimensional H(q) and D(e)(q) as q → 0, and the divergence is of a different functional form from that predicted for the diffusion coefficient in one-component one-dimensional and two-dimensional fluids not subject to boundary conditions that define the dimensionality of the system. We provide support for the contention that the boundary conditions that define a confined system play a very important role in determining the long-wavelength behavior of the collective diffusion coefficient from two sources: (i) the results of simulations of H(q) and D(e)(q) in quasi-1D and quasi-2D systems and (ii) verification, using data from the work of Lin, Rice and Weitz [Phys. Rev. E 51, 423 (1995)], of the prediction by Bleibel et al., arXiv:1305.3715, that D(e)(q) for a monolayer of colloid particles constrained to lie in the interface between two fluids diverges as q(-1) as q → 0.

Are buckyballs hydrophobic?

Buckyballs exhibit two seemingly opposing characters. On one hand, they are known to be insoluble in water with all potential chemical properties of being hydrophobic. On the other hand, their pairwise effective interaction in water includes a repulsive solvent-induced contribution. We perform molecular dynamics simulations of the association process of two C60 fullerenes in water at different temperatures in order to reconcile these contradicting observations. For comparison, the simulations were also performed in a nonpolar solvent, and the results were further contrasted with those obtained previously for the association of graphene sheets. Considering the association in water, we find small magnitudes for the enthalpy and entropy changes with small positive slopes as a function of temperature, implying an almost negligible change in the heat capacity at constant pressure. These findings sharply contradict the behavior of typical hydrophobic interactions. The reason for these abnormalities, as well as for the repulsive nature of the solvent-induced interactions, is the shape of the contact state that supports the existence of a distinct type of interfacial waters located between two convex surfaces of two buckyballs. These interfacial waters are characterized by smaller entropy and lower density and form a smaller number of hydrogen bonds with surrounding waters compared with those of the interfacial waters around the dissociated solutes. Thus, upon bringing the C60 fullerenes into contact, the changes associated with the liberation of the latter to bulk waters are opposed by the concomitant conversion of the latter also to the distinct waters between the two spherical solutes. We argue that although the effective pair interaction is not hydrophobic, the solvation properties are hydrophobic. In the hydration free energy of a single solute, there is no contact state. Furthermore, in the solubility at the macroscopic scale, the relative number of these distinct waters around a large aggregate is smaller, and hence, they are not predicted to influence much the solvation properties. Therefore, buckyballs can serve as an example in which hydrophobic interaction cannot be deducted from hydrophobic solvation.

Side-chain-side-chain interactions and stability of the helical state.

Understanding the driving forces that lead to the stability of the secondary motifs found in proteins, namely α-helix and ß-sheet, is a major goal in structural biology. The thermodynamic stability of these repetitive units is a result of a delicate balance between many factors, which in addition to the peptide chain involves also the solvent. Despite the fact that the backbones of all amino acids are the same (except of that of proline), there are large differences in the propensity of the different amino acids to promote the helical structure. In this paper, we investigate by explicit-solvent molecular dynamics simulations the role of the side chains (modeled as coarse-grained single sites) in stabilizing α helices in an aqueous solution. Our model systems include four (six-mer-nine-mer) peptide lengths in which the magnitude of the effective attraction between the side chains is systematically increased. We find that these interactions between the side chains can induce (for the nine-mer almost completely) a transition from a coil to a helical state. This transition is found to be characterized by three states in which the intermediate state is a partially folded α-helical conformation. In the absence of any interactions between the side chains the free energy change for helix formation has a small positive value indicating that favorable contributions from the side chains are necessary to stabilize the helical conformation. Thus, the helix-coil transition is controlled by the effective potentials between the side-chain residues and the magnitude of the required attraction per residue, which is on the order of the thermal energy, reduces with the length of the peptide. Surprisingly, the plots of the population of the helical state (or the change in the free energy for helix formation) as a function of the total effective interactions between the side chains in the helical state for all peptide lengths fall on the same curve.

Dual base-flipping of cytosines in a CpG dinucleotide sequence.

Simultaneous flipped-out conformation of two neighboring bases on opposite strands of DNAs has been observed in several X-ray structures. It has also been detected for two cytosines on opposite strands in different contexts of CpG sites. In this paper, we study by MD simulations the dual base flipping of the two cytosines in hemi-methylated CpG site. We calculate the potential of mean force of flipping-out the unmethylated cytosine in three model systems. The first is for DNA bound to the regulatory protein UHRF1. In this case, the methyl-cytosine on the complementary strand is flipped-out into the binding pocket of the SRA domain of the protein. The other two systems are for unbound DNAs in which the methyl-cytosine is either intra-helical or extra-helical. We find that when the methyl-cytosine is flipped-out it is easier to flip-out the other (unmethylated) cytosine on the opposite strand by about 14-16kJ/mol. This lower penalty for dual-base flipping is observed for both the bound and unbound states of the DNA. Analyses of the hydrogen bond network and stacking interactions within the CpG site indicate that the lower penalty is due to stabilization of the dual-base flipped-out conformation via interactions involving the orphan guanines. The results presented in this paper suggest that the extra-helical conformation of the methyl-cytosine recognized by UHRF1 can facilitate the base-flipping process of the target cytosine to be methylated by Dnmt1.

Aggregation and cooperative effects in the aldol reactions of lithium enolates.

Density functional theory and Car-Parrinello molecular dynamics simulations have been carried out for model aldol reactions involving aggregates of lithium enolates derived from acetaldehyde and acetone. Formaldehyde and acetone have been used as electrophiles. It is found that the geometries of the enolate aggregates are in general determined by the most favorable arrangements of the point charges within the respective Lin On clusters. The reactivity of the enolates follows the sequence monomer≫dimer>tetramer. In lithium aggregates, the initially formed aldol adducts must rearrange to form more stable structures in which the enolate and alkoxide oxygen atoms are within the respective Lin On clusters. Positive cooperative effects, similar to allosteric effects found in several proteins, are found for the successive aldol reactions in aggregates. The corresponding transition structures show in general sofa geometries.

Propensities for loop structures of RNA & DNA backbones.

RNA oligonucleotides exhibit a large tendency to bend and form a loop conformation which is a major motif contributing to their complex three-dimensional structure. This is in contrast to DNA molecules that predominantly form the double-helix structure. In this paper we investigate by molecular dynamics simulation, as well as, by its combination with the replica-exchange method, the propensity of RNA chains containing the GCUAA pentaloop to form spontaneously a hairpin conformation. The results were then compared with those of analogous hybrid oligonucleotides in which the ribose groups in the loop-region were substituted by deoxyriboses. We find that the RNA oligomers exhibit a marginal excess stability to form loop structures. The equilibrium constant for opening the loop to an extended conformation is twice as large in the hybrid than it is in the RNA chain. Analyses of the hydrogen bonds indicate that the excess stability for forming a hairpin is a result of hydrogen bonds the 2'-hydroxyls in the loop region form with other groups in the loop. Of these hydrogen bonds, the most important is the hydrogen bond donated from the 2'-OH at the first position of the loop to N7 of adenine at the forth position. RNA and DNA backbones are characterized by different backbone dihedral angles and sugar puckering that can potentially facilitate or hamper the hydrogen bonds involving the 2'-OH. Nevertheless, the sugar puckerings of all the pentaloop nucleotides were not significantly different between the two chains displaying the C3'-endo conformation characteristic to the A-form double helix. All of the other backbone dihedrals also did not show any considerable difference in the loop-region except of the δ-dihedral. In this case, the RNA loop exhibited bimodal distributions corresponding to, both, the RNA and DNA backbones, whereas the loop of the hybrid chain behaved mostly as that of a DNA backbone. Thus, it is possible that the behavior of the δ-dihedrals in the loop-region of the RNA adopts conformations that facilitate the intra-nucleotide hydrogen bondings of the 2'-hydroxyls, and consequently renders loop structures in RNA more stable.

Base-flipping propensities of unmethylated, hemimethylated, and fully methylated CpG sites.

Methylation of C5 of cytosines at CpG dinucleotide sites of the DNA is one of the most important factors regulating the expression of genes. The interactions of these CpG sites with proteins are essential for recognition and catalysis and in many cases are characterized by the flipping of either of the cytosine bases out of the DNA helix. In this paper, we present results from molecular dynamics simulations indicating that methylation of CpG sites suppresses spontaneous extra-helical conformations of either of the two cytosines. Thus, cytosines in unmethylated sites flip out easier than in hemimethylated sites and the latter flip out easier than in fully methylated sites. The different propensities for base flipping is observed not only between the cytosines that differ in their methylation states but also between the cytosines on the complementary strand. From alchemical mutation calculations, we find that methylation of one of the cytosines increases the free energy of the extra-helical conformation by 10.3-16.5 kJ/mol and this increase is additive with respect to the second methylation. Potential of mean force calculations confirm these results and reveal that cytosines in unmethylated sites favor flipping via the major-groove pathway. We perform several analyses to correlate this behavior with structural changes induced by the different methylation states of the CpG site. However, we demonstrate that the driving force for these propensities is the change in the electronic distribution around the pyrimidine ring upon methylation. In particular, unmethylated cytosine interacts more favorably (primarily via electrostatic forces) with solvent water molecules than methylated cytosine. This is observed for, both, extra-helical cytosines and intra-helical cytosines in which the cytosine on the complementary strand flips out and water molecules enter the DNA double-helix and substitute the hydrogen bonds with the orphan guanine. On the basis of these results of spontaneous base flipping, we conjecture that the mechanism for base flipping observed in complexes between hemimethylated DNAs and proteins is not likely to be passive.