Coarse-Grained Protein Model Coupled with a Coarse-Grained Water Model: Molecular Dynamics Study of Polyalanine-Based Peptides

The coupling of a coarse-grained (CG) protein model with the CG water model developed by Marrink et al. (J. Phys. Chem. B 2004, 108, 750) is presented. The model was used in the molecular dynamics studies of Ac-(Ala)6-Xaa-(Ala)7-NHMe, Xaa = Ala, Leu, Val, and Gly. A Gly mutation in the middle of polyalanine is found to destabilize the helix and stabilize the hairpin by favoring a type-II‘ turn and probably to speed up hairpin folding. The simulations allow us to derive thermodynamic parameters of, in particular, the helical propensities (s) of amino acids in these polyalanine-based peptides. The calculated s values are 1.18 (Ala), 0.84 (Leu), 0.30 (Val), and <0.02 (Gly) at 291 K, in excellent agreement with experimental values (R2=0.970). Analyses using a structural approach method show that the helical propensity difference of these amino acids mainly comes from solvation effect. Leu and Val have lower helical propensities than Ala mainly because the larger side chains shield the solvation of helical structures, while Gly has a much poorer helical propensity mainly due to the much better solvation for the coil structures than for the helical structures. Overall, the model is at least about 102 times faster than current all-atom MD methods with explicit solvent

A Strand-Loop-Strand Structure Is a Possible Intermediate in Fibril Elongation: Long Time Simulations of Amyloid-β Peptide (10−35)

A total of 6.2 μs molecular dynamics simulations of amyloid-β (10−35) (Aβ) were performed in explicit water solvent. The results reveal that the collapsed-coil (cc) structure determined by experiments is stable at pH 5.6 for hundreds of nanoseconds, but it can exchange with a strand-loop-strand (SLS) structure on the microsecond time scale. The SLS structure has D23−K28 as a reverse loop and the central hydrophobic core and the C-terminal in hydrophobic contact. This SLS structure topologically resembles the proposed monomer conformation in fibrils. Since it has been suggested that a special conformation of Aβ is needed when the monomer binds to fibril ends to elongate fibrils, we propose that the SLS structure may be an important intermediate binding structure for Aβ fibril growth. Simulations at pH 2.0, which is used to mimic the mutation of E22Q and D23N, and at high temperature (400 K) indicate that the SLS structure is considerably populated under these conditions while the cc structure is disrupted. These results imply that the SLS structures may also be a binding intermediate in other conditions such as E22Q and/or D23N mutations and high temperature, which have been proved to promote fibril formation previously

Theoretical Studies on Ru-Catalyzed Pauson−Khand-Type [2+2+1] and Related [2+2+1+1] Cycloadditions

Density functional theory (DFT) calculations have been carried out to understand the mechanism of the Ru3(CO)12-catalyzed Pauson−Khand-type [2+2+1] reaction and related [2+2+1+1] cycloadditions. The geometries were optimized using the BP86/6-31G*(SDD for Ru) method, and the energies were evaluated with the 6-311+G*(SDD) basis set. We found that these reactions are initiated by a CO−alkyne coupling, forming a ruthenacyclobutenone intermediate, and the widely accepted alkene−alkyne coupling pathway has a much higher activation energy. In the intermolecular reaction between alkene and alkyne, the formation of quinones and hydroquinones through [2+2+1+1] cycloadditions is more favorable than the Pauson−Khand-type reaction, while the intramolecular reaction with 1,6-enyne leads to a favorable Pauson−Khand-type reaction. These results are in agreement with experimental observations. For the [2+2+1+1] cycloadditions we found that the formation of quinones is favored over the formation of hydroquinones due to the preferred insertion of alkynes, which can be attributed to the preferred orbital interaction between the π orbital of the alkyne moiety and the d orbital of the metal center

A Theoretical Study on the Mechanism of the Reductive Half-Reaction of Xanthine Oxidase

On the basis of the crystal structure of an aldehyde oxidoreductase, Huber et al. proposed a catalytic mechanism for the reductive half-reaction of xanthine oxidase which involves nucleophilic addition of Mo-bound hydroxide (Moco 1) to the substrate and hydride transfer from the substrate to sulfido group (MoS). Density functional theory calculations have been carried out for the oxidation of formaldehyde, acetaldehyde, formamide, and formamidine with Moco 2 to understand more detailed catalytic pathways. Our calculation results indicate that the anionic catalyst model acts as a nucleophile and is reactive for the oxidation of aldehyde substrates, which are reactive for nucleophilic addition. In these cases, a concerted mechanism is found to be more favorable than a stepwise mechanism. The concerted mechanism is further shown to be promoted by the presence of a nearby water molecule, in the active site, which serves as a Lewis acid for the nucleophilic addition of hydroxide. For less reactive formamide and formamidine (a model for xanthine) substrates, the calculated activation energies with the above mechanisms are high. These reactions also do not benefit from the presence of the water molecule. The results indicate that different catalyst forms might be responsible for the oxidation of different substrates, which could be regulated by the enzyme active site environment

Folding of Fourteen Small Proteins with a Residue-Specific Force Field and Replica-Exchange Molecular Dynamics

Ab initio protein folding via physical-based all-atom simulation is still quite challenging. Using a recently developed residue-specific force field (RSFF1) in explicit solvent, we are able to fold a diverse set of 14 model proteins. The obtained structural features of unfolded state are in good agreement with previous observations. The replica-exchange molecular dynamics simulation is found to be efficient, resulting in multiple folding events for each protein. Transition path time is found to be significantly reduced under elevated temperature

A Theoretical Study on the Origin of Cooperativity in the Formation of 3₁₀- and α-Helices

By using a simple repeating unit method, we have conducted a theoretical study which delineates the preferences for β-strand, 27-ribbon, 310-helix, and α-helix formation for a series of polyglycine models up to 14 amino acid residues (Ac-(Gly)n, n = 0, 1, 2, ..., 14). Interactions among residues, which result in cooperativity, are clearly indicated by variations in calculated energies of the residues. Whereas no cooperativity is found in the formation of β-strands and 27-ribbons, there is a significant cooperativity in the formation of 310- and α-helices, especially for the latter. In the case of α-helices, the 14th residue is more stable than the 3rd by about 3 kcal/mol. A good correlation between calculated residue energy and residue dipole moment was uncovered, indicating the importance of long-range electrostatic interactions to the cooperativity. The results of our calculations are compared with those of the AMBER and PM3 methods, and indicate that both methods, AMBER and PM3, need further development in the cooperative view of electrostatic interactions. The result should be of importance in providing insight into protein folding and formation of helical structures in a variety of polymeric compounds. This also suggests a strategy for the development of more consistent molecular mechanics force fields

A Theoretical Study of the Mechanisms and Regiochemistry of the Reactions of 5-Alkoxyoxazole with Thioaldehydes, Nitroso Compounds, and Aldehydes

A theoretical study based on B3LYP/6-31G* calculations has been applied to the mechanisms and regiochemistry of reactions of 5-alkoxyoxazole with thioaldehydes, nitroso compounds, and aldehydes. All three reactions adopt similar mechanisms, which start with Diels−Alder (DA) reactions, followed by either a novel, concerted ring-opening−ring-closing (RORC) step to transfer the DA adduct to 2-alkoxycarbonyl-3-thiazoline and 2-alkoxycarbonyl-3-oxazoline for thioaldehydes and aldehydes, respectively, or stepwise ring-opening and ring-closing steps to generate 1,2,4-oxadiazoline for nitroso compounds. The reactions of 5-alkoxyoxazole with thioaldehydes and nitroso compounds can be conducted under thermal reaction conditions due to the 10 kcal/mol activation barriers for their rate-determining DA reactions. By contrast, the reaction of 5-alkoxyoxazole with aldehydes cannot take place under thermal conditions, since this bimolecular reaction has the rate-determining RORC transition state higher than the reactants by 30.5 kcal/mol

Theoretical Studies of <i>β</i>-Peptide Models

The key conformations of β-dipeptide models 4−9 have been studied with quantum mechanics calculations including a self-consistent isodensity solvation model to evaluate the tendency of β-sheet, 14-helix, and 12-helix formation of β-peptide models. The most stable conformation of dipeptide models 5−7 is a formal six-membered-ring (C6) hydrogen-bonded structure, although the hydrogen bond is very weak because of a bad N−H- - -O angle. Many local conformational minima with folded structures are found. This is attributed to internal non-hydrogen-bonded electrostatic (or dipole) interactions. Most interestingly, for dipeptide model 7, the most stable conformation in polar solvent is predicted to correspond to the 14-helix. The conformations for β-sheet, 14-helix, and 12-helix are much destabilized by electrostatic interactions in the gas phase but significantly benefit from the polar solvent effect. The 12-helix is intrinsically less favorable than the 14-helix. The key difference between 14- and 12-helices is the dihedral angle (μ) about the Cα−Cβ bondthe former is about 60° while the latter is about 90°. Comparatively, β3-peptides have greater 14-helical propensity than β2-peptides. The five-membered and six-membered rings in dipeptide models 8 and 9 promote the 12-helix and 14-helix conformations, respectively. Calculations for β-hexapeptide models 10 and 11 indicate somewhat stronger hydrogen bonding in the 12-helix than in the 14-helix structure

A Theoretical Study on the Mechanism and Diastereoselectivity of the Kulinkovich Hydroxycyclopropanation Reaction

A detailed mechanism for the Kulinkovich hydroxycyclopropanation reaction has been explored with density functional theory calculations on the reactions between R1COOMe and Ti(OMe)2(CH2CHR2) (R1 and R2 are hydrogen and alkyl groups). Addition of ester to titanacyclopropane is found to be fast, exothermic, and irreversible. It has a preference for the α-addition manifold over the β-addition manifold in which its cycloinsertion transition states suffer from the steric repulsion between the R2 and ester. The following intramolecular methoxy migration step is also exothermic with reasonable activation energy. The cyclopropane-forming step is the rate-determining step, which affords the experimentally observed cis-R1/R2 diastereoselectivity in the α-addition manifold by generating cis-R1/R2 1,2-disubstituted cyclopropanol when R1 is primary alkyl groups. On the contrary, the unfavored β-addition manifold offers the diastereoselectivity contradicting the experimental observations. The effects of R1 and R2 on the regio- and stereoselectivity are also discussed

A Theoretical Study on the Structure of Poly((<i>R</i>)-3-hydroxybutanoic acid)

Conformational features of oligomers of 3-(R)-butanoic acid have been studied using quantum mechanics methods. Conformational search of Ac−OCH(CH3)−CH2−COOCH3 indicates that the compound is quite flexible with several conformations similar in stability. Study of Ac−[OCH(CH3)−CH2−CO]nOCH2CH3, n = 1−8, using a repeating unit approach for 21-helix, 31-helix, 41-helix, 51-helix, and pleated strand structure indicates that only the 31-helix has a cooperative effect and is also most stable. Crystal orbital calculations on the crystal packing energies of the 21-, 31-, and 41-helices have been performed. The 21-helix is found to have much stronger crystal packing stabilization than the 31- and 41-helices. This explains why the 21-helix is found in crystal structures of poly((R)-3-hydroxybutanoic acid) (PHB) despite the fact that the 31-helix is the most stable single helix. The stabilization of the 21-helix in the crystal structure is mainly from the dipole interaction between adjacent parallel helices but not from adjacent antiparallel helices. The study also provides useful information for the study of ion channel structures of PHB