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At least 1,279 records · Page 71Linked to original sources
PubMed2003

Theoretical perspectives on the reaction mechanism of serine proteases: the reaction free energy profiles of the acylation process.

The reaction mechanism of serine proteases (trypsin), which catalyze peptide hydrolysis, is studied theoretically by ab initio QM/MM electronic structure calculations combined with Molecular Dynamics-Free Energy Perturbation calculations. We have calculated the entire reaction free energy profiles of the first reaction step of this enzyme (acylation process). The present calculations show that the rate-determining step of the acylation is the formation of the tetrahedral intermediate, and the breakdown of this intermediate has a small energy barrier. The calculated activation free energy for the acylation is approximately 17.8 kcal/mol at QM/MM MP2/(aug)-cc-pVDZ//HF/6-31(+)G/AMBER level, and this reaction is an exothermic process. MD simulations of the enzyme-substrate (ES) complex and the free enzyme in aqueous phase show that the substrate binding induces slight conformational changes around the active site, which favor the alignment of the reactive fragments (His57, Asp102, and Ser195) together in a reactive orientation. It is also shown that the proton transfer from Ser195 to His57 and the nucleophilic attack of Ser195 to the carbonyl carbon of the scissile bond of the substrate occur in a concerted manner. In this reaction, protein environment plays a crucial role to lowering the activation free energy by stabilizing the tetrahedral intermediate compared to the ES complex. The polarization energy calculations show that the enzyme active site is in a very polar environment because of the polar main chain contributions of protein. Also, the ground-state destabilization effect (steric strain) is not a major catalytic factor. The most important catalytic factor of stabilizing the tetrahedral intermediate is the electrostatic interaction between the active site and particular regions of protein: the main chain NH groups in Gly193 and Ser195 (so-called oxyanion hole region) stabilize negative charge generated on the carbonyl oxygen of the scissile bond, and the main chain carbonyl groups in Ile212 approximately Ser214 stabilize a positive charge generated on the imidazole ring of His57.

Binding Sites↗
PubMed2002

Squaryl group as a new mimic of phosphate group in modified oligodeoxynucleotides: synthesis and properties of new oligodeoxynucleotide analogues containing an internucleotidic squaryldiamide linkage.

This paper describes the synthesis and properties of a new type of modified oligodeoxynucleotide containing a neutral but highly polarized squaryl group as a novel mimic of the phosphate group. A modified thymidine dimer derivative (TsqT) having a squaryldiamide linkage was synthesized in almost quantitative yield by a two-step substitution of diethyl squarate with 3'-amino-5'-O-(4,4'-dimethoxytrityl)-3'-deoxythymidine and 5'-amino-5'-deoxythymidine. The CD and UV studies of TsqT suggest that this dimer has basically a structure similar to that of TpT. The NMR studies of TsqT show a unique property, namely, that the squaryl group of TsqT is influenced by Mg2+ concentration. The ab initio calculations of TsqT showed a highly polarized structure resembling that of a phosphate group. This dimer structural motif was finally incorporated into oligodeoxynucleotides by use of the phosphoramidite approach. The hybridization affinity of these modified oligodeoxynucleotides for the complementary and mismatched oligodeoxynucleotides was studied in detail by using Tm experiments. Consequently, it turned out that in a matched duplex of 5'-d(CGCATsqTAGCC)-3'/5'-d(GGCTAATGCG)-3' the A-T base pairs at the modified site can be preserved, but instead thermal destabilization of the overall structure was observed. To estimate the structure of the duplex, two kinds of fluorescein chromophores (fluorescein (FL) and cyanine 3 (Cy3)) were introduced into the 5'-terminal site of 5'-d(GACGCATsqTAGCCGAT)-3' and 5'-d(ATCGGCTAATGCGTC)-3', respectively. The fluorescence resonance energy transfer experiments using these functionalized oligodeoxynucleotides suggest that the matched duplexes have a bent structure at the modified site. This conclusion was also strongly supported by computational MM and MD simulations.

Amides↗
PubMed2003

2D conformationally sampled pharmacophore: a ligand-based pharmacophore to differentiate delta opioid agonists from antagonists.

Pharmacophores are widely used for rational drug design and include those based on receptor binding sites or on known ligands. To date, ligand-based pharmacophores have typically used one or a small number of conformers of known receptor ligands. However, this method does not take into account the inherent dynamic nature of molecules, which sample a wide range of conformations, any of which could be the bound form. In the present study, molecular dynamics (MD) simulations were used as a means to sample the conformational space of ligands to include all accessible conformers at room temperature in the development of a pharmacophore. On the basis of these conformers, probability distributions of selected distances and angles in a series of delta specific opioid ligands were obtained and correlated with agonist versus antagonist activities. Individually, the distributions did not allow for unique agonist and antagonist pharmacophores to be identified. However, by extending the conformational analysis to two dimensions, a 2D conformationally sampled pharmacophore (CSP) for distinguishing delta receptor agonists and antagonists was developed. Application of this model to the compound DPI2505 suggests that it may have agonist activity. It is anticipated that the CSP method, which does not require alignment of compounds during pharmacophore development, will be a useful tool for obtaining structure-function relationships of ligands particularly in systems where the receptor 3D structure is not known.

Computer Simulation↗
PubMed2003

8-Oxoguanine enhances bending of DNA that favors binding to glycosylases.

Molecular dynamics (MD) simulations were carried out on the DNA oligonucleotide GGGAACAACTAG:CTAGTTGTTCCC in its native form and with guanine in the central G(19):C(6) base pair replaced by 8-oxoguanine (8oxoG). A box of explicit water molecules was used for solvation, and Na(+) counterions were added to neutralize the system. The direction and magnitude of global bending were assessed by a technique used previously to analyze simulations of DNA containing a thymine dimer. The presence of 8oxoG did not greatly affect the magnitude of DNA bending; however, bending into the major groove was significantly more probable when 8oxoG replaced G(19). Crystal structures of glycosylases bound to damaged-DNA substrates consistently show a sharp bend into the major groove at the damage site. We conclude that changes in bending dynamics that assist the formation of this kink are a part of the mechanism by which glycosylases of the base excision repair pathway recognize the presence of 8oxoG in DNA.

DNA↗
PubMed2004

Role of Asp102 in the catalytic relay system of serine proteases: a theoretical study.

The role of Asp102 in the catalytic relay system of serine proteases is studied theoretically by calculating the free energy profiles of the single proton-transfer reaction by the Asn102 mutant trypsin and the concerted double proton-transfer reaction (so-called the charge-relay mechanism) of the wild-type trypsin. For each reaction, the reaction free energy profile of the rate-determining step (the tetrahedral intermediate formation step) is calculated by using ab initio QM/MM electronic structure calculations combined with molecular dynamics-free energy perturbation method. In the mutant reaction, the free energy monotonically increases along the reaction path. The rate-determining step of the mutant reaction is the formation of tetrahedral intermediate complex, not the base (His57) abstraction of the proton from Ser195. In contrast to the single proton-transfer reaction of the wild-type, MD simulations of the enzyme-substrate complex show that the catalytically favorable alignment of the relay system (the hydrogen bonding network between the mutant triad, His57, Asn102, and Ser195) is rarely observed even in the presence of a substrate at the active site. In the double proton-transfer reaction, the energy barrier is observed at the proton abstraction step, which corresponds to the rate-determining step of the single proton-transfer reaction of the wild-type. Although both reaction profiles show an increase of the activation barrier by several kcals/mol, these increases have different energetic origins: a large energetic loss of the electrostatic stabilization between His57 and Asn102 in the mutant reaction, while the lack of stabilization by the protein environment in the double proton-transfer reaction. Comparing the present results with the single proton transfer of the wild-type, Asp102 is proven to play two important roles in the catalytic process. One is to stabilize the protonated His57, or ionic intermediate, formed during the acylation, and the other is to fix the configuration around the active site, which is favorable to promote the catalytic process. These two factors are closely related to each other and are indispensable for the efficient catalysis. Also the present calculations suggest the importance of the remote site interaction between His57 and Val213-Ser214 at the catalytic transition state.

Aspartic Acid↗
PubMed2004

Gas-phase hydrogen/deuterium exchange and conformations of deprotonated flavonoids and gas-phase acidities of flavonoids.

Gas-phase hydrogen/deuterium (H/D) exchange was used to probe the conformations, gas-phase acidities, and sites of deprotonation of isomeric flavonoid aglycons and glycosides. The flavonoids in each isomer series were differentiated on the basis of their relative rate constants and total numbers of exchanges. For example, flavonoids that possess neohesperidose-type disaccharides may undergo faster and far more extensive exchange than isomeric rutinoside flavonoids. The structural factors that promote or prevent H/D exchange were identified and correlated with collisionally activated dissociation (CAD) patterns and/or molecular modeling data (both high-level ab initio acidity calculations and conformational analysis with molecular dynamics (MD) simulations), thus providing a framework for the use of H/D exchange reactions in the structural elucidation of new flavonoids.

Carbohydrates↗
PubMed2003

In silico studies of the mechanism of methanol oxidation by quinoprotein methanol dehydrogenase.

The mechanism of bacterial methanol dehydrogenase involves hydride equivalent transfer from substrate to the ortho-quinone PQQ to provide a C5-reduced intermediate that subsequently rearranges to the hydroquinone PQQH(2). We have studied the PQQ reduction by molecular dynamic (MD) simulations in aqueous solution. Among the five simulated structures, either Asp297 or Glu171 or both are ionized. Reasonable structures are obtained only when both carboxyl groups are ionized. This is not unexpected since the kinetic pH optimum is 9.0. In the structure of the enzyme.PQQ.HOCH(3) complex, the hydrogen bonded Glu171-CO(2)(-).H-OCH(3) is in a position to act as a general base catalyst for hydride equivalent transfer to C5 of PQQ. We thus suggest that Glu171 plays the role of general base catalyst in PQQ reduction rather than Asp297 as previously suggested. The reduction is assisted by Arg324, which hydrogen bonds to the ortho-quinone moiety of PQQ. The rearrangement of the C5-reduced intermediate to provide hydroquinone PQQH(2) is also assisted by proton abstraction by Glu171-CO(2)(-) and the continuous hydrogen bonding of Arg324 throughout the entire reaction. These features as well as the mapping of the channel for substrate and water into the active site entrance are the observations of major importance.

Alcohol Oxidoreductases↗
PubMed2003

Glycine on a wet pyrite surface at extreme conditions.

We present ab initio molecular dynamics (MD) simulations of the simplest amino acid, glycine, at the water/pyrite interface under extreme pressure/temperature conditions. These simulations are aimed to contribute to the discussion of the "iron-sulfur world" (ISW) scenario, an intriguing proposal in the controversial field of "Origin of Life" research. The simulations show that glycine easily desorbs from a water/pyrite interface through hydrogen-bond assistance. The retention time is only of the order of a picosecond, and the surface bonding is best understood as a relatively weak electrostatic interaction. However, we have found indications of glycine activation due to the interaction with the surface, and thus for a possible reaction with a suitable anchor molecule.

Journal Article↗
PubMed2004

The structure of aqueous guanidinium chloride solutions.

The combination of neutron diffraction with isotopic substitution (NDIS) experiments and molecular dynamics (MD) simulations to characterize the structuring in an aqueous solution of the denaturant guanidinium chloride is described. The simulations and experiments were carried out at a concentration of 3 m at room temperature, allowing for an examination of any propensity for ion association in a realistic solution environment. The simulations satisfactorily reproduced the principal features of the neutron scattering and indicate a bimodal hydration of the guanidinium ions, with the N-H groups making well-ordered hydrogen bonds in the molecular plane, but with the planar faces relatively deficient in interactions with water. The most striking feature of these solutions is the rich ion-ion ordering observed around the guanidinium ion in the simulations. The marked tendency of the guanidinium ions to stack parallel to their water-deficient surfaces indicates that the efficiency of this ion as a denaturant is due to its ability to simultaneously interact favorably with both water and hydrophobic side chains of proteins.

Cations↗
PubMed2005

N,N'-linked oligoureas as foldamers: chain length requirements for helix formation in protic solvent investigated by circular dichroism, NMR spectroscopy, and molecular dynamics.

N,N'-linked oligoureas with proteinogenic side chains are peptide backbone mimetics belonging to the gamma-peptide lineage. In pyridine, heptamer 4 adopts a stable helical fold reminiscent of the 2.6(14) helical structure proposed for gamma-peptide foldamers. In the present study, we have used a combination of CD and NMR spectroscopies to correlate far-UV chiroptical properties and conformational preferences of oligoureas as a function of chain length from tetramer to nonamer. Both the intensity of the CD spectra and NMR chemical shift differences between alphaCH2 diastereotopic protons experienced a marked increase for oligomers between four and seven residues. No major change in CD spectra occurred between seven and nine residues, thus suggesting that seven residues could be the minimum length required for stabilizing a dominant conformation. Unexpectedly, in-depth NMR conformational investigation of heptamer 4 in CD3OH revealed that the 2.5 helix probably coexists with partially (un)folded conformations and that Z-E urea isomerization occurs, to some degree, along the backbone. Removing unfavorable electrostatic interactions at the amino terminal end of 4 and adding one H-bond acceptor by acylation with alkyl isocyanate (4 --> 7) was found to reinforce the 2.5 helical population. The stability of the 2.5 helical fold in MeOH is further discussed in light of unrestrained molecular dynamics (MD) simulation. Taken together, these new data provide additional insight into the folding propensity of oligoureas in protic solvent and should be of practical value for the design of helical bioactive oligoureas.

Biomimetic Materials↗
PubMed2005

Mechanism of ligand exchange studied using transition path sampling.

The mechanism of intermolecular ligand exchange has been studied using transition path sampling (TPS) based molecular dynamics (MD) simulations. Specifically, the exchange of solvent molecules bound to unsaturated Cr(CO)5 in methanol solution has been investigated. The results of the TPS simulations have shown that there are multiple steps in the reaction mechanism. The first involves partial dissociation of the coordinated solvent from the Cr metal center followed by association with a new methanol molecule between the normally void first and second solvent layers. After diffusive motion of the exchanging ligands, the last step involves the originally bound methanol molecule moving into the bath continuum followed by solvation of the Cr metal fragment by the exchanging ligand. It has been found that the reaction center (defined as the organometallic fragment and two exchanging ligands only) and the solvent bath have favorable interactions. This is likely due to the adiabatic nature of the ligand exchange transition. The ability to understand the microscopic molecular dynamics of a chemical process based on a free energy analysis is also discussed.

Journal Article↗
PubMed2004

Cooperative motions of protein and hydration water molecules: molecular dynamics study of scytalone dehydratase.

Two molecular dynamics (MD) simulations totaling 25 ns of simulation time of monomeric scytalone dehydratase (SD) were performed. The enzyme has a ligand-binding pocket containing a cone-shaped alpha+beta barrel, and the C-terminal region covers the binding pocket. Our simulations clarified the difference in protein dynamics and conformation between the liganded protein and the unliganded protein. The liganded protein held the ligand molecule tightly and the initial structure was maintained during the simulation. The unliganded protein, on the other hand, fluctuated dynamically and its structure changed largely from the initial structure. In the equilibrium state, the binding pocket was fully solvated by opening of the C-terminal region, and the protein dynamics was connected with hydration water molecules entry into and release from the binding pocket. In addition, the cooperative motions of the unliganded protein and the hydration water molecules produced the path through the protein interior for ligand binding.

Computer Simulation↗
PubMed2004

Computational study of the ground state of thermophilic indole glycerol phosphate synthase: structural alterations at the active site with temperature.

Hyperthermophlic indole-3-glycerol phosphate synthase (IGPS) catalyzes the terminal ring-closure step in tryptophan biosynthesis. In this paper, we compare the results from the molecular dynamics (MD) simulation of enzyme-bound substrate at 298 K (E.S298) and 385 K (E.S385) solvated in the TIP3P water box using the CHARMM force field to address the question of the structural change of the Enzyme. Substrate complex with temperature. The population of the reactive Enzyme. Substrate conformers (near attack conformers or NACs) increases by approximately 1100-fold in going from room temperature (E.S298) to high temperature (E.S385). This increased population of NAC conformers in the Michaelis complex correlates well with the increase in rate in going from 298 to 385 K. The positioning of the two active site residues Lys53 and Lys110 controls binding of the substrate in the favorable orientation for general acid-catalyzed intramolecular ring formation reaction. It can be concluded that the NAC formation allowing general acid catalysis has much to do with the temperature dependence of the free energy of reaction.

Archaea↗
PubMed2005

Picosecond dynamics of ligand interconversion in the primary docking site of heme proteins.

We have used femtosecond IR spectroscopy to probe interconversion dynamics of ligand in the primary docking site of heme proteins under physiological conditions. The docking site, fashioned with highly conserved amino acid residues, modulates ligand-binding activity by mediating the passage of ligand to and from the active binding site. Ligands in two states of the docking site interconvert on the picosecond time scale, and the rates are about 4 times slower in hemoglobin than that in myoglobin. The accurate interconversion rates on the time scale readily accessible by MD simulations can be used to refine computer simulations, which could in turn provide a detailed mechanistic picture of ligand binding in heme proteins.

Animals↗
PubMed2005

Structure and dynamics of solvated Sn(II) in aqueous solution: an ab initio QM/MM MD approach.

Structural and dynamical properties of the hydrated Sn(II) ion have been investigated by ab initio quantum mechanical/molecular mechanical (QM/MM) molecular dynamics (MD) simulations at double-zeta HF quantum mechanical level. The results indicate Sn(II)aq to be a rather peculiar, if not unique, case of a hydrated ion: four of its eight first-shell ligands do not take place in the otherwise frequent ligand-exchange processes, forming an approximately tetrahedral cage around the ion. The remaining ligands, however, exchange at a rate that is rather comparable to monovalent than divalent ions. This very surprising behavior of ligand exchange not yet observed in any previous simulation of over 30 hydrated metal ions is consistently confirmed by vibrational spectra, bond lengths, and a detailed analysis of the trajectories of the simulation.

Computer Simulation↗
PubMed2005

Dynamical arrest of electron transfer reorganization in super-cooled water.

This paper reports the results of Molecular Dynamics (MD) simulations of the solvent reorganization energy of electron transfer (ET) reactions in low-temperature solvents. Simulations are carried out for a model charge-transfer optical dye (p-nitroaniline) in SPC/E water in a range of temperatures down to the point of solvent ideal glass transition. We show a significant departure of the solvent reorganization energy, measured on a given time window, from its thermodynamic limit obtained by averaging over long simulation trajectories. Our results thus indicate that optical solvatochromism and activation parameters of ET reactions measured in viscous solvents will be significantly affected by the dynamical arrest of nuclear solvation when the experimental time scale becomes comparable to the characteristic relaxation time of the solvent.

Journal Article↗
PubMed2005

A simple method to predict protein flexibility using secondary chemical shifts.

Protein motions play a critical role in many biological processes, such as enzyme catalysis, allosteric regulation, antigen-antibody interactions, and protein-DNA binding. NMR spectroscopy occupies a unique place among methods for investigating protein dynamics due to its ability to provide site-specific information about protein motions over a large range of time scales. However, most NMR methods require a detailed knowledge of the 3D structure and/or the collection of additional experimental data (NOEs, T1, T2, etc.) to accurately measure protein dynamics. Here we present a simple method based on chemical shift data that allows accurate, quantitative, site-specific mapping of protein backbone mobility without the need of a three-dimensional structure or the collection and analysis of NMR relaxation data. Further, we show that this chemical shift method is able to quantitatively predict per-residue RMSD values (from both MD simulations and NMR structural ensembles) as well as model-free backbone order parameters.

Carbon Isotopes↗