Ab initio molecular dynamics study of solvated electrons in methanol clusters.

We performed a series of ab initio molecular dynamics simulations to investigate the physical properties of small methanol cluster anions, [(CH3OH)n]-, (n = 8-32). An excess electron was attached to neutral clusters that were prepared to accommodate the electron in interior cavity states or surface bound states. The computed initial binding energies of the electrons to these clusters indicate appealing similarity to the experimentally observed vertical detachment energies. The tendency of the interior state clusters parallels that of the clusters with strong electron binding in the experiments, while the simulated unrelaxed surface state anions are similar to the observed weakly bound species. This assignment is consistent with a previous identification based on hybrid quantum-classical simulations. The time evolution of the cluster anions suggests that interior state electrons slowly move to and relax on the surface, in excess electronic states that appear significantly more stable than the experimentally assigned putative surface states. Based on this result we predict the existence of relaxed surface state isomers of small methanol cluster anions. Due to the kinetic metastability of the experimentally found weakly bound species, we anticipate a serious technical challenge to prepare and identify small methanol cluster anions with relaxed surface states. These more strongly binding surface states are stabilized by dangling hydroxyl hydrogen atoms pointing to the excess electron's charge distribution. In addition, methyl hydrogens also appear to contribute to the stability of these states. During its transition to the surface, the interior excess electron maintains its initial solvent cavity. No signs of non-cavity interior states are observed in the present first principles ab initio molecular dynamics simulations.

Excess electrons in methanol clusters: Beyond the one-electron picture.

We performed a series of comparative quantum chemical calculations on various size negatively charged methanol clusters, CH3OHn-. The clusters are examined in their optimized geometries (n = 2-4), and in geometries taken from mixed quantum-classical molecular dynamics simulations at finite temperature (n = 2-128). These latter structures model potential electron binding sites in methanol clusters and in bulk methanol. In particular, we compute the vertical detachment energy (VDE) of an excess electron from increasing size methanol cluster anions using quantum chemical computations at various levels of theory including a one-electron pseudopotential model, several density functional theory (DFT) based methods, MP2 and coupled-cluster CCSD(T) calculations. The results suggest that at least four methanol molecules are needed to bind an excess electron on a hydrogen bonded methanol chain in a dipole bound state. Larger methanol clusters are able to form stronger interactions with an excess electron. The two simulated excess electron binding motifs in methanol clusters, interior and surface states, correlate well with distinct, experimentally found VDE tendencies with size. Interior states in a solvent cavity are stabilized significantly stronger than electron states on cluster surfaces. Although we find that all the examined quantum chemistry methods more or less overestimate the strength of the experimental excess electron stabilization, MP2, LC-BLYP, and BHandHLYP methods with diffuse basis sets provide a significantly better estimate of the VDE than traditional DFT methods (BLYP, B3LYP, X3LYP, PBE0). A comparison to the better performing many electron methods indicates that the examined one-electron pseudopotential can be reasonably used in simulations for systems of larger size.

Alternative chelator for 89Zr radiopharmaceuticals: radiolabeling and evaluation of 3,4,3-(LI-1,2-HOPO).

Zirconium-89 is an effective radionuclide for antibody-based positron emission tomography (PET) imaging because its physical half-life (78.41 h) matches the biological half-life of IgG antibodies. Desferrioxamine (DFO) is currently the preferred chelator for (89)Zr(4+); however, accumulation of (89)Zr in the bones of mice suggests that (89)Zr(4+) is released from DFO in vivo. An improved chelator for (89)Zr(4+) could eliminate the release of osteophilic (89)Zr(4+) and lead to a safer PET tracer with reduced background radiation dose. Herein, we present an octadentate chelator 3,4,3-(LI-1,2-HOPO) (or HOPO) as a potentially superior alternative to DFO. The HOPO ligand formed a 1:1 Zr-HOPO complex that was evaluated experimentally and theoretically. The stability of (89)Zr-HOPO matched or surpassed that of (89)Zr-DFO in every experiment. In healthy mice, (89)Zr-HOPO cleared the body rapidly with no signs of demetalation. Ultimately, HOPO has the potential to replace DFO as the chelator of choice for (89)Zr-based PET imaging agents.

Capping amyloid ß-sheets of the tau-amyloid structure VQIVYK with hexapeptides designed to arrest growth. An ONIOM and density functional theory study.

We present ONIOM calculations using density functional theory (DFT) as the high and AM1 as the medium level that explore the abilities of different hexapeptide sequences to terminate the growth of a model for the tau-amyloid implicated in Alzheimer's disease. We delineate and explore several design principles (H-bonding in the side chains, using antiparallel interactions on the growing edge of a parallel sheet, using all-d residues to form rippled interactions at the edge of the sheet, and replacing the H-bond donor N-H's that inhibit further growth) that can be used individually and in combination to design such peptides that will have a greater affinity for binding to the parallel ß-sheet of acetyl-VQIVYK-NHCH3 than the natural sequence and will prevent another strand from binding to the sheet, thus providing a cap to the growing sheet that arrests further growth. We found peptides in which the Q is replaced by an acetyllysine (aK) residue to be particularly promising candidates, particularly if the reverse sequence (KYVIaKV) is used to form an antiparallel interaction with the sheet.

Capping parallel ß-sheets of acetyl(Ala)6NH2 with an acetyl(Ala)5ProNH2 can arrest the growth of the sheet, suggesting a potential for curtailing amyloid growth. An ONIOM and density functional theory study.

We present ONIOM calculations using B3LYP/d95(d,p) as the high level and AM1 as the medium level on parallel ß-sheets containing four strands of Ac-AAAAAA-NH2 capped with either Ac-AAPAAA-NH2 or Ac-AAAPAA-NH2. Because Pro can form H-bonds from only one side of the peptide linkage (that containing the C═O H-bond acceptor), only one of the two Pro-containing strands can favorably add to the sheet on each side. Surprisingly, when the sheet is capped with AAPAAA-NH2 at one edge, the interaction between the cap and sheet is slightly more stabilizing than that of another all Ala strand. Breaking down the interaction enthalpies into H-bonding and distortion energies shows the favorable interaction to be due to lower distortion energies in both the strand and the four-stranded sheet. Because another strand would be inhibited for attachment to the other side of the capping (Pro-containing) strand, we suggest the possible use of Pro residues in peptides designed to arrest the growth of many amyloids.

The interactions of phenylalanines in ß-sheet-like structures from molecular orbital calculations using density functional theory (DFT), MP2, and CCSD(T) methods.

We present density functional theory calculations designed to evaluate the importance of π-stacking interactions to the stability of in-register Phe residues within parallel ß-sheets, such as amyloids. We have used a model of a parallel H-bonded tetramer of acetylPheNH2 as a model and both functionals that were specifically designed to incorporate dispersion effects (DFs), as well as, several traditional functionals which have not been so designed. None of the functionals finds a global minimum for the π-stacked conformation, although two of the DFs find this to be a local minimum. The stacked phenyls taken from the optimized geometries calculated for each functional have been evaluated using MP2 and CCSD(T) calculations for comparison. The results suggest that π-stacking does not make an important contribution to the stability of this system and (by implication) to amyloid formation.

Foldamers of ß-peptides: conformational preference of peptides formed by rigid building blocks. The first MI-IR spectra of a triamide nanosystem.

To determine local chirality driven conformational preferences of small aminocyclobutane-1-carboxylic acid derivatives, X-(ACBA) n -Y, their matrix-isolation IR spectra were recorded and analyzed. For the very first time model systems of this kind were deposited in a frozen (~10 K) noble gas matrix to reduce line width and thus, the recorded sharp vibrational lines were analyzed in details. For cis-(S,R)-1 monomer two "zigzag" conformers composed of either a six or an eight-membered H-bonded pseudo ring was identified. For trans-(S,S)-2 stereoisomer a zigzag of an eight-membered pseudo ring and a helical building unit were determined. Both findings are fully consistent with our computational results, even though the relative conformational ratios were found to vary with respect to measurements. For the dimers (S,R,S,S)-3 and (S,S,S,R)-4 as many as four different cis,trans and three different trans,cis conformers were localized in their matrix-isolation IR (MI-IR) spectra. These foldamers not only agree with the previous computational and NMR results, but also unambiguously show for the first time the presence of a structure made of a cis,trans conformer which links a "zigzag" and a helical foldamer via a bifurcated H-bond. The present work underlines the importance of MI-IR spectroscopy, applied for the first time for triamides to analyze the conformational pool of small biomolecules. We have shown that the local chirality of a ß-amino acid can fully control its backbone folding preferences. Unlike proteogenic α-peptides, ß- and especially (ACBA) n type oligopeptides could thus be used to rationally design and influence foldamer's structural preferences.

Secondary structure of short ß-peptides as the chiral expression of monomeric building units: a rational and predictive model.

Chirality of the monomeric residues controls and determines the prevalent folding of small oligopeptides (from di- to tetramers) composed of 2-aminocyclobutane-1-carboxylic acid (ACBA) derivatives with the same or different absolute and relative configuration. The cis-form of the monomeric ACBA gives rise to two conformers, namely, Z6 and Z8, while the trans-form manifests uniquely as an H8 structure. By combining these subunits in oligo- and polypeptides, their local structural preference remains, thus allowing the rational design of new short foldamers. A lego-type molecular architecture evolves; the overall look depends only on the conformational properties of the structural building units. A versatile and efficient method to predict the backbone folds of designed cyclobutane ß-peptides is based on QM calculations. Predictions are corroborated by high-resolution NMR studies on selected stereoisomers, most of them being new foldamers that have been synthesized and characterized for the first time. Thus, the chiral expression of monomeric building units results in the defined secondary structures of small oligomers. As a result of this study, a new set of chirality controlled foldamers is provided to probe as biocompatible biopolymers.

Density functional theory study of ß-hairpins in antiparallel ß-sheets, a new classification based upon H-bond topology.

We present a new classification of ß-turns specific to antiparallel ß-sheets based upon the topology of H-bond formation. This classification results from ONIOM calculations using B3LYP/D95** density functional theory and AM1 semiempirical calculations as the high and low levels, respectively. We chose acetyl(Ala)(6)NH(2) as a model system as it is the simplest all-alanine system that can form all the H-bonds required for a ß-turn in a sheet. Of the 10 different conformations we have found, the most stable structures have C(7) cyclic H-bonds in place of the C(10) interactions specified in the classic definition. Also, the chiralities specified for residues i + 1 and i + 2 in the classic definition disappear when the structures are optimized using our techniques, as the energetic differences among the four diastereomers of each structure are not substantial for 8 of the 10 conformations.

Exploiting diverse stereochemistry of ß-amino acids: toward a rational design of sheet-forming ß-peptide systems.

Due to the two methylene groups in their backbone, ß-amino acids can adopt numerous secondary structures, including helices, sheets and nanotubes. Chirality introduced by the additional side chains can significantly influence the folding preference of ß-peptides composed of chiral ß-amino acids. However, only conceptual suggestions are present in the literature about the effect of chirality on folding preferences. Summarizing both the experimental and computational results, Seebach (Chem Biodivers 1:1111-1240, 2004) has proposed the first selection rule on the effect of side chain chirality, on the folding preference of ß-peptides. In order to extend and fine-tune the aforementioned predictions of Seebach, we have investigated its validity to the novel type of apolar sheet proposed recently (Pohl et al. in J Phys Chem B 114:9338-9348, 2010). In order to facilitate the rational design of sheet-like structures, a systematic study on the effect of chirality on "apolar" sheet stability is presented on disubstituted [HCO-ß-Ala-ß(2,3)-hAla-ß-Ala-NH(2)](2) model peptides calculated at the M05-2X/6-311++G(d,p)//M05-2X/6-31G(d) and B3LYP/6-311++G(d,p)//B3LYP/6-31G(d) levels of theory both in vacuum and in polar and apolar solvents. In addition, both types of "apolar" sheets were investigated; the one with two strands of identical (AA) and enantiomeric (AB) backbone structure. Our results show that heterochirally disubstituted sheets have the greatest preference for sheet formation (ΔG ~ -11 kcal mol(-1)). However, in contrast to Seebach's predictions, "homochiral disubstitution" itself does not necessarily disrupt the sheet structure, rather it could result stable fold (ΔG ~ -5 kcal mol(-1)). Results indicate that both the methyl group orientation and the local conformational effect of substitution affects sheet stability, as point chirality was found to have influence only on the backbone torsional angles. These results enabled us to extend and generalize Seebach's predictions and to propose a more general and accurate "rule of thumb" describing the effect of chirality on sheet stability. This offers an easy-to-use summary on how to design ß-peptide sheet structures. We conclude that heterochirally disubstituted models are the best candidates for sheet formation, if the two strands are substituted in a way to create identical torsional angle sets on the two backbones for ideal hydrogen-bonding pattern. With adequately selected side chains, homochirally disubtituted derivatives may also form sheet structures, and the position of methyl groups would prevent assembly of more than two strands making it ideal to create hairpins.

The role of entropy in initializing the aggregation of peptides: a first principle study on oligopeptide oligomerization.

The initiation and progression of Alzheimer's disease is coupled to the oligo- and polymerization of amyloid peptides in the brain. Amyloid like aggregates of protein domains were found practically independent of their primary sequences. Thus, the driving force of the transformation from the original to a disordered amyloid fold is expected to lie in the protein backbone common to all proteins. In order to investigate the thermodynamics of oligomerization, full geometry optimizations and frequency calculations were performed both on parallel and antiparallel ß-pleated sheet model structures of [HCO-(Ala)(1-6)-NH(2)](2) and (For-Ala(1-2)-NH(2))(1-6) peptides, both at the B3LYP and M05-2X/6-311++G(d,p)//M05-2X/6-31G(d) levels of theory, both in vacuum and in water. Our results show that relative entropy and enthalpy both show a hyperbolic decrease with increasing residue number and with increasing number of strands as well. Thus, di- and oligomerization are always thermodynamically favored. Antiparallel arrangements were found to have greater stability than parallel arrangements of the polypeptide backbones. During our study the relative changes in thermodynamic functions are found to be constant for long enough peptides, indicating that stability and entropy terms are predictable. All thermodynamic functions of antiparallel di- and oligomers show a staggered nature along the increasing residue number. By identifying and analyzing the 6 newly emerging dimer vibrational modes of the 10- and 14-membered building units, the staggered nature of the entropy function can be rationalized. Thus, the vanishing rotational and translational modes with respect to single strands are converted into entropy terms "holding tight" the dimers and oligomers formed, rationalizing the intrinsic adherence of natural polypeptide backbones to aggregate.

Extended apolar beta-peptide foldamers: the role of axis chirality on beta-peptide sheet stability.

This study is on structure and stability of sheetlike conformers of beta-peptides; never seen new foldamers are reported here for the first time. Single- and double-stranded structures are analyzed, and the seeds of large beta-layers and biocompatible nanomaterials are described here. Both the monomeric, HCO-[NH-CH(2)-CH(2)CO](n)-NH(2), and dimeric forms, [HCO-(beta-Ala)(n)-NH(2)](2) n = 3 and 4, of oligo-beta-alanine supramolecular complexes are evaluated by using an adequate level of theory M052X/6-31G(d) for peptides of this size. Polymers composed of backbone foldamers with the central mu torsion angle set to an anti orientation were all probed. Sheet structures built up of strands with carbonyl groups monotonically facing the same spatial direction, polar strands, were previously assigned and synthesized ( Seebach , D. Chem. Biodiversity 2004 , 1 , 1111 - 1239 ). Now we are presenting a novel beta-peptide sheet structure of alternating carbonyl group orientations, called as apolar strands. These novel secondary structural elements of beta-peptides are structural analogs of beta-pleated sheets of proteins. Interestingly enough, the latter type of apolar strands are foreseen as very stable supramolecular complexes and are more firm by approximately 10 kcal.mol(-1) than the aforementioned polar strands. Furthermore, apolar strands lack the inherent twisting of beta-layers, present in polar strands resulting in the tubular shape. Once the effect of substitution of Hbeta1 and/or Hbeta2 atoms are revealed on foldamer stability, short peptide sequence could be designed and synthesized. These new, conformationally optimized beta-sheetlike nanostructures of increased stability with little or no twisting could be used as enzymatically resistant ( Frackenpohl , J. , Arvidsson , P. I. , Schreiber , J. V. , and Seebach , D. ChemBioChem 2001 , 2 , 445 - 455 ) biomaterials. These newly designed models systems could enlarge the arsenal of durable polyesters of similar chemical constitution (e.g., -[O-CH(CH(3))-CH(2)CO](n)- and -[O-CH(COOH)-CH(2)CO](n)-) already used as artificial heart valves, for example.

A matrix isolation study on Ac-Gly-NHMe and Ac-l-Ala-NHMe, the simplest chiral and achiral building blocks of peptides and proteins.

The infrared absorption (IR) spectra of acetyl-N-methyl-glycine and acetyl-N-methyl-alanine have been recorded in dichloromethane and dimethyl sulfoxide-d(6) solution, as well as in Ar and Kr matrices. The spectra were assigned with the help of quantum chemical calculations. Based on the assignments of the matrix-isolation IR spectra, in line with theoretical predictions, two different hydrogen bonded conformers were identified, furthermore a third conformer is likely to be present, which cannot be unambiguously identified. In dichloromethane two conformers could be observed, while in dimethyl sulfoxide a single conformer could be identified. Vibrational circular dichroism (VCD) spectra of acetyl-N-methyl-l-alanine have also been recorded in solutions and matrices. These matrix-isolation VCD spectra not only support the assignments of the matrix-isolation IR spectra, but also demonstrate that these spectra can be interpreted much easier with the help of quantum chemical calculations than the VCD spectra recorded in solutions. It is also shown that the rotatory strength of some vibrational transitions changes rapidly as a function of the backbone torsional coordinates; hence the appearance of some regions in the VCD spectra is extremely dependent on any perturbations, e.g. weak intermolecular interactions.

Prediction of folding preference of 10 kDa silk-like proteins using a Lego approach and ab initio calculations.

Because of their great flexibility and strength resistance, both spider silks and silkworm silks are of increasing scientific and commercial interest. Despite numerous spectroscopic and theoretical studies, several structural properties at the atomic level have yet to be identified. The present theoretical investigation focuses on these issues by studying three silk-like model peptides: (AG)(64), [(AG)(4)EG](16), and [(AG)(4)PEG](16), using a Lego-type approach to construct these polypeptides. On the basis of these examples it is shown that thermoneutral isodesmic reactions and ab initio calculations provide a capable method to investigate structural properties of repetitive polypeptides. The most probable overall fold schema of these molecules with respect to the type of embedded hairpin structures were determined at the ab initio level of theory (RHF/6-311++G(d,p)//RHF/3-21G). Further on, analysis is carried out on the possible hairpin and turn regions and on their effect on the global fold. In the case of the (AG)(64) model peptide, the optimal beta-sheet/turn ratio was also determined, which provided good support for experimental observations. In addition, lateral shearing of a hairpin "folding unit" was investigated at the quantum chemical level to explain the mechanical properties of spider silk. The unique mechanical characteristics of silk bio-compounds are now investigated at the atomic level.