Structure and thermodynamics of H3O+(H2O)8 clusters: A combined molecular dynamics and quantum mechanics approach

We have studied the structure and stability of (H3O+)(H2O)8 clusters using a combination of molecular dynamics sampling and high-level ab initio calculations. 20 distinct oxygen frameworks are found within 2 kcal/mol of the electronic or standard Gibbs free energy minimum. The impact of quantum zero-point vibrational corrections on the relative stability of these isomers is quite significant. The box-like isomers are favored in terms of electronic energy, but with the inclusion of zero-point vibrational corrections and entropic effects tree-like isomers are favored at higher temperatures. Under conditions from 0 to 298.15 K, the global minimum is predicted to be a tree-like structure with one dangling singly coordinated water molecule. Above 298.15 K, higher entropy tree-like isomers with two or more singly coordinated water molecules are favored. These assignments are generally consistent with experimental IR spectra of (H3O+)(H2O)8 obtained at 150 K.

Molecular Dynamics Simulation of a PNA·DNA·PNA Triple Helix in Aqueous Solution

Molecular dynamics simulations have been used to explore the conformational flexibility of a PNA·DNA·PNA triple helix in aqueous solution. Three 1.05 ns trajectories starting from different but reasonable conformations have been generated and analyzed in detail. All three trajectories converge within about 300 ps to produce stable and very similar conformational ensembles, which resemble the crystal structure conformation in many details. However, in contrast to the crystal structure, there is a tendency for the direct hydrogen-bonds observed between the amide hydrogens of the Hoogsteen-binding PNA strand and the phosphate oxygens of the DNA strand to be replaced by water-mediated hydrogen bonds, which also involve pyrimidine O2 atoms. This structural transition does not appear to weaken the triplex structure but alters groove widths and so may relate to the potential for recognition of such structures by other ligands (small molecules or proteins). Energetic analysis leads us to conclude that the reason that the hybrid PNA/DNA triplex has quite different helical characteristics from the all-DNA triplex is not because the additional flexibility imparted by the replacement of sugar−phosphate by PNA backbones allows motions to improve base-stacking but rather that base-stacking interactions are very similar in both types of triplex and the driving force comes from weak but definate conformational preferences of the PNA strands.

Molecular Dynamics Simulations of the d(TAT) Triple Helix

Molecular dynamics (MD) simulations have been used to study the dynamical and time-averaged characteristics of the DNA triple helix d(T)10âd(A)10âd(T)10. The structures sampled during the trajectory resemble closely the B-type model for the DNA triplex proposed on the basis of NMR data, although there are some subtle differences. Alternative P- and A-type conformations for the triplex, suggested from X-ray experiments, are not predicted to contribute significantly to the structure of the DNA triplex in solution. Comparison with the best available experimental data supports the correctnes of the MD-generated structures. The analysis of the collected data gives a detailed picture of the characteristics of triple-helix DNA. A new and interesting pattern of hydration, specific for triplex DNA, is an important observation. The results suggest that molecular dynamics can be useful for the study of novel nucleic acid structures.

Ramachandran-type Plots for Glycosidic Linkages: Examples from Molecular Dynamics Simulations using the Glycam06 Force Field

The goals of this article are to (1) provide further validation of the Glycam06 force field, specifically for its use in implicit solvent molecular dynamic (MD) simulations, and (2) to present the extension of G.N. Ramachandran's idea of plotting amino acid phi and psi angles to the glycosidic phi, psi, and omega angles formed between carbohydrates. As in traditional Ramachandran plots, these carbohydrate Ramachandran-type (carb-Rama) plots reveal the coupling between the glycosidic angles by displaying the allowed and disallowed conformational space. Considering two-bond glycosidic linkages, there are 18 possible conformational regions that can be defined by (α, ϕ, ψ) and (β, ϕ, ψ), whereas for three-bond linkages, there are 54 possible regions that can be defined by (α, ϕ, ψ, ω) and (β, ϕ, ψ, ω). Illustrating these ideas are molecular dynamic simulations on an implicitly hydrated oligosaccharide (700 ns) and its eight constituent disaccharides (50 ns/disaccharide). For each linkage, we compare and contrast the oligosaccharide and respective disaccharide carb-Rama plots, validate the simulations and the Glycam06 force field through comparison to experimental data, and discuss the general trends observed in the plots.

Quantum Mechanical Study of Sulfuric Acid Hydration: Atmospheric Implications

The role of the binary nucleation of sulfuric acid in aerosol formation and its implications for global warming is one of the fundamental unsettled questions in atmospheric chemistry. We have investigated the thermodynamics of sulfuric acid hydration using ab initio quantum mechanical methods. For H2SO4(H2O)n where n = 1–6, we used a scheme combining molecular dynamics configurational sampling with high-level ab initio calculations to locate the global and many low lying local minima for each cluster size. For each isomer, we extrapolated the Møller–Plesset perturbation theory (MP2) energies to their complete basis set (CBS) limit and added finite temperature corrections within the rigid-rotor-harmonic-oscillator (RRHO) model using scaled harmonic vibrational frequencies. We found that ionic pair (HSO4–·H3O+)(H2O)n−1 clusters are competitive with the neutral (H2SO4)(H2O)n clusters for n ≥ 3 and are more stable than neutral clusters for n ≥ 4 depending on the temperature. The Boltzmann averaged Gibbs free energies for the formation of H2SO4(H2O)n clusters are favorable in colder regions of the troposphere (T = 216.65–273.15 K) for n = 1–6, but the formation of clusters with n ≥ 5 is not favorable at higher (T > 273.15 K) temperatures. Our results suggest the critical cluster of a binary H2SO4–H2O system must contain more than one H2SO4 and are in concert with recent findings(1) that the role of binary nucleation is small at ambient conditions, but significant at colder regions of the troposphere. Overall, the results support the idea that binary nucleation of sulfuric acid and water cannot account for nucleation of sulfuric acid in the lower troposphere.

Hydration of the Bisulfate Ion: Atmospheric Implications

Using molecular dynamics configurational sampling combined with ab initio energy calculations, we determined the low energy isomers of the bisulfate hydrates. We calculated the CCSD(T) complete basis set (CBS) binding electronic and Gibbs free energies for 53 low energy isomers of HSO4–(H2O)n=1–6 and derived the thermodynamics of adding waters sequentially to the bisulfate ion and its hydrates. Comparing the HSO4–/H2O system to the neutral H2SO4/H2O cluster, water binds more strongly to the anion than it does to the neutral molecules. The difference in the binding thermodynamics of HSO4–/H2O and H2SO4/H2O systems decreases with increasing number of waters. The thermodynamics for the formation of HSO4–(H2O)n=1–5 is favorable at 298.15 K, and that of HSO4–(H2O)n=1–6 is favorable for T < 273.15 K. The HSO4– ion is almost always hydrated at temperatures and relative humidity values encountered in the troposphere. Because the bisulfate ion binds more strongly to sulfuric acid than it does to water, it is expected to play a role in ion-induced nucleation by forming a strong complex with sulfuric acid and water, thus facilitating the formation of a critical nucleus.

Quantum Mechanical Study of Sulfuric Acid Hydration: Atmospheric Implications

The role of the binary nucleation of sulfuric acid in aerosol formation and its implications for global warming is one of the fundamental unsettled questions in atmospheric chemistry. We have investigated the thermodynamics of sulfuric acid hydration using ab initio quantum mechanical methods. For H2SO4(H2O)n where n = 1–6, we used a scheme combining molecular dynamics configurational sampling with high-level ab initio calculations to locate the global and many low lying local minima for each cluster size. For each isomer, we extrapolated the Møller–Plesset perturbation theory (MP2) energies to their complete basis set (CBS) limit and added finite temperature corrections within the rigid-rotor-harmonic-oscillator (RRHO) model using scaled harmonic vibrational frequencies. We found that ionic pair (HSO4–·H3O+)(H2O)n−1clusters are competitive with the neutral (H2SO4)(H2O)n clusters for n ≥ 3 and are more stable than neutral clusters for n ≥ 4 depending on the temperature. The Boltzmann averaged Gibbs free energies for the formation of H2SO4(H2O)n clusters are favorable in colder regions of the troposphere (T = 216.65–273.15 K) for n = 1–6, but the formation of clusters with n ≥ 5 is not favorable at higher (T > 273.15 K) temperatures. Our results suggest the critical cluster of a binary H2SO4–H2O system must contain more than one H2SO4 and are in concert with recent findings(1) that the role of binary nucleation is small at ambient conditions, but significant at colder regions of the troposphere. Overall, the results support the idea that binary nucleation of sulfuric acid and water cannot account for nucleation of sulfuric acid in the lower troposphere.

Hydration of the Sulfuric Acid−Methylamine Complex and Implications for Aerosol Formation

The binary H2SO4−H2O nucleation is one of the most important pathways by which aerosols form in the atmosphere, and the presence of ternary species like amines increases aerosol formation rates. In this study, we focus on the hydration of a ternary system of sulfuric acid (H2SO4), methylamine (NH2CH3), and up to six waters to evaluate its implications for aerosol formation. By combining molecular dynamics (MD) sampling with high-level ab initio calculations, we determine the thermodynamics of forming H2SO4(NH2CH3)(H2O)n, where n = 0−6. Because it is a strong acid−base system, H2SO4−NH2CH3 quickly forms a tightly bound HSO4−−NH3CH3+ complex that condenses water more readily than H2SO4 alone. The electronic binding energy of H2SO4−NH2CH3 is −21.8 kcal mol−1 compared with −16.8 kcal mol−1 for H2SO4−NH3 and −12.8 kcal mol−1 for H2SO4−H2O. Adding one to two water molecules to the H2SO4−NH2CH3 complex is more favorable than adding to H2SO4 alone, yet there is no systematic difference for n ≥ 3. However, the average number of water molecules around H2SO4−NH2CH3 is consistently higher than that of H2SO4, and it is fairly independent of temperature and relative humidity.

Hydration of the Sulfuric Acid-Methylamine Complex and Implications for Aerosol Formation

The binary H2SO4-H2O nucleation is one of the most important pathways by which aerosols form in the atmosphere, and the presence of ternary species like amines increases aerosol formation rates. In this study, we focus on the hydration of a ternary system of sulfuric acid (H2SO4), methylamine (NH2CH3), and up to six waters to evaluate its implications for aerosol formation. By combining molecular dynamics (MD) sampling with high-level ab initio calculations, we determine the thermodynamics of forming H2SO4(NH2CH3)(H2O)n, where n = 0-6. Because it is a strong acid-base system, H2SO4-NH2CH3 quickly forms a tightly bound HSO4(-)-NH3CH3(+) complex that condenses water more readily than H2SO4 alone. The electronic binding energy of H2SO4-NH2CH3 is -21.8 kcal mol(-1) compared with -16.8 kcal mol(-1) for H2SO4-NH3 and -12.8 kcal mol(-1) for H2SO4-H2O. Adding one to two water molecules to the H2SO4-NH2CH3 complex is more favorable than adding to H2SO4 alone, yet there is no systematic difference for n ≥ 3. However, the average number of water molecules around H2SO4-NH2CH3 is consistently higher than that of H2SO4, and it is fairly independent of temperature and relative humidity.

Benchmark Structures and Binding Energies of Small Water Clusters with Anharmonicity Corrections

For (H2O)n where n = 1–10, we used a scheme combining molecular dynamics sampling with high level ab initio calculations to locate the global and many low lying local minima for each cluster. For each isomer, we extrapolated the RI-MP2 energies to their complete basis set limit, included a CCSD(T) correction using a smaller basis set and added finite temperature corrections within the rigid-rotor-harmonic-oscillator (RRHO) model using scaled and unscaled harmonic vibrational frequencies. The vibrational scaling factors were determined specifically for water clusters by comparing harmonic frequencies with VPT2 fundamental frequencies. We find the CCSD(T) correction to the RI-MP2 binding energy to be small (<1%) but still important in determining accurate conformational energies. Anharmonic corrections are found to be non-negligble; they do not alter the energetic ordering of isomers, but they do lower the free energies of formation of the water clusters by as much as 4 kcal/mol at 298.15 K.

Benchmark Structures and Binding Energies of Small Water Clusters with Anharmonicity Corrections

For (H2O)n where n = 1–10, we used a scheme combining molecular dynamics sampling with high level ab initio calculations to locate the global and many low lying local minima for each cluster. For each isomer, we extrapolated the RI-MP2 energies to their complete basis set limit, included a CCSD(T) correction using a smaller basis set and added finite temperature corrections within the rigid-rotor-harmonic-oscillator (RRHO) model using scaled and unscaled harmonic vibrational frequencies. The vibrational scaling factors were determined specifically for water clusters by comparing harmonic frequencies with VPT2 fundamental frequencies. We find the CCSD(T) correction to the RI-MP2 binding energy to be small (

Accurate Predictions of Water Cluster Formation, (H2O)n=2-10

An efficient mixed molecular dynamics/quantum mechanics model has been applied to the water cluster system. The use of the MP2 method and correlation consistent basis sets, with appropriate correction for BSSE, allows for the accurate calculation of electronic and free energies for the formation of clusters of 2−10 water molecules. This approach reveals new low energy conformers for (H2O)n=7,9,10. The water heptamer conformers comprise five different structural motifs ranging from a three-dimensional prism to a quasi-planar book structure. A prism-like structure is favored energetically at low temperatures, but a chair-like structure is the global Gibbs free energy minimum past 200 K. The water nonamers exhibit less complexity with all the low energy structures shaped like a prism. The decamer has 30 conformers that are within 2 kcal/mol of the Gibbs free energy minimum structure at 298 K. These structures are categorized into four conformer classes, and a pentagonal prism is the most stable structure from 0 to 320 K. Results can be used as benchmark values for empirical water models and density functionals, and the method can be applied to larger water clusters.

The Search for Low Energy Conformational Families of Small Peptides: Searching for Active Conformations of Small Peptides in the Absence of a Known Receptor

Breast cancer is the most common cancer among women. Tamoxifen is the preferred drug for estrogen receptor-positive breast cancer treatment, yet many of these cancers are intrinsically resistant to tamoxifen or acquire resistance during treatment. Therefore, scientists are searching for breast cancer drugs that have different molecular targets. Previous work revealed that 8-mer and cyclic 9-mer peptides inhibit breast cancer in mouse and rat model systems, interacting with an unknown receptor, while peptides smaller than eight amino acids did not inhibit breast cancer. We have shown that the use of replica exchange molecular dynamics predicts structure and dynamics of active peptides, leading to the discovery of smaller peptides with full biological activity. These simulations identified smaller peptide analogs with a conserved turn, a β-turn formed in the larger peptides. These analogs inhibit estrogen-dependent cell growth in a mouse uterine growth assay, a test showing reliable correlation with human breast cancer inhibition. We outline the computational methods that were tried and used with the experimental information that led to the successful completion of this research.

Computational Design and Experimental Discovery of an Anti-estrogenic Peptide Derived from Alpha-Fetoprotein

Breast cancer is the most common cancer among women, and tamoxifen is the preferred drug for estrogen receptor-positive breast cancer treatment. Many of these cancers are intrinsically resistant to tamoxifen or acquire resistance during treatment. Consequently, there is an ongoing need for breast cancer drugs that have different molecular targets. Previous work has shown that 8-mer and cyclic 9-mer peptides inhibit breast cancer in mouse and rat models, interacting with an unsolved receptor, while peptides smaller than eight amino acids did not. We show that the use of replica exchange molecular dynamics predicts the structure and dynamics of active peptides, leading to the discovery of smaller peptides with full biological activity. Simulations identified smaller peptide analogues with the same conserved reverse turn demonstrated in the larger peptides. These analogues were synthesized and shown to inhibit estrogen-dependent cell growth in a mouse uterine growth assay, a test showing reliable correlation with human breast cancer inhibition.

In search of CS2(H2O)n = 1–4 clusters

Gaussian-3 and MP2/aug-cc-pVnZ methods have been used to calculate geometries and thermochemistry of CS2(H2O)n, where n = 1–4. An extensive molecular dynamics search followed by optimization using these two methods located two dimers, six trimers, six tetramers, and two pentamers. The MP2/aug-cc-pVDZ structure matched best with the experimental result for the CS2(H2O) dimer, showing that diffuse functions are necessary to model the interactions found in this complex. For larger CS2(H2O)n clusters, the MP2/aug-cc-pVDZ minima are significantly different from the MP2(full)/6-31G* structures, revealing that the G3 model chemistry is not suitable for investigation of sulfur containing van der Waals complexes. Based on the MP2/aug-cc-pVTZ free energies, the concentration of saturated water in the atmosphere and the average amount of CS2 in the atmosphere, the concentrations of these clusters are predicted to be on the order of 105CS2(H2O) clusters∙cm−3 and 102 CS2(H2O)2 clusters∙cm−3 at 298.15 K. The MP2/aug-cc-pVDZ scaled harmonic and anharmonic frequencies of the most abundant dimer cluster at 298 K are presented, along with the MP2/aug-cc-pVDZ scaled harmonic frequencies for the CS2(H2O)n structures predicted to be present in a low-temperature molecular beam experiment.