Conformational Energy Changes Research Articles

How to Personalize General Anesthesia-A Prospective Theoretical Approach to Conformational Changes of Halogenated Anesthetics in Fire Smoke Poisoning.

Smoke intoxication is a central event in mass burn incidents, and toxic smoke acts at different levels of the body, blocking breathing and oxygenation. The majority of these patients require early induction of anesthesia to preserve vital functions. We studied the influence of hemoglobin (HMG) and myoglobin (MGB) blockade by hydrochloric acid (HCl) in an interaction model with gaseous anesthetics using molecular docking techniques. In the next part of the study, molecular dynamics (MD) simulations were performed on the top-scoring ligand-receptor complexes to investigate the stability of the ligand-receptor complexes and the interactions between ligands and receptors in more detail. Through docking analysis, we observed that hemoglobin creates more stable complexes with anesthetic gases than myoglobin. Intoxication with gaseous hydrochloric acid produces conformational and binding energy changes of anesthetic gases to the substrate (both the pathway and the binding site), the most significant being recorded in the case of desflurane and sevoflurane, while for halothane and isoflurane, they remain unchanged. According to our theoretical model, the selection of anesthetic agents for patients affected by fire smoke containing hydrochloric acid is critical to ensure optimal anesthetic effects. In this regard, our model suggests that halothane and isoflurane are the most suitable choices for predicting the anesthetic effects in such patients when compared to sevoflurane and desflurane.

Stimulus responsive luminescence and application of rotor type 1,1′-([2,2′-bithiophene]-3,3′-diyl)bis(ethan-1-one) and 3′-acetyl-[2,2′-bithiophene]-3-carbaldehyde as molecular rotors

Two dithiophene aldehyde/ketone derivatives are designed as luminescence molecular rotors, i.e., 1,1′-([2,2′-bithiophene]-3,3′-diyl)bis(ethan-1-one) (BTBE) and 3′-acetyl-[2,2′-bithiophene]-3-carbaldehyde (BTAC). Their absorption and luminescence properties, as well as the stimulus responsive luminescence characteristics of water spikes are studied in detail. In order to further explore relationship of luminescence and molecular structure, three reference compounds are also synthesized, named 1-(2-methylthiophen-3-yl)ethanone (MTE), 2-methylthiophene-3-carbaldehyde (MTC) and 4H-cyclohepta[1,2-b:7,6-b’]dithiophen-4-one (CDTO). BTBE and BTAC have two obvious absorption bands in the short wavelength region with peak wavelengths of about 212 nm and 260 nm, respectively, while there is a weak trailing type absorption band in the range of about 300–400 nm. Their fluorescence spectra show two luminescence bands in the range of 280–350 nm and 400–600 nm, respectively, and the latter is stronger. Compared with the absorption and luminescence spectra of the reference compounds, it is determined that two absorption bands of BTBE and BTAC in shorter wavelength region are derived from the single thiophene ring carbonyl planar unit, while the absorption band in longer region are derived from the integrated structure of dithiophene carbonyl. The fluorescence bands with peaks of about 300 nm and 470 nm originate respectively from the localized F-C vertical excited states (LE), i.e., the excited state from single planar thienyl-carbonyl unit, and integrated excited state (IE), i.e., the excited state from integrated di-thienyl-carbonyl rings linked covalently with less dihedral angle and greater degree of conjugation at excited state. The crystal structure data show that two thiophene rings possess larger dihedral angles in crystal states, 86.9° for BTBE and 60.8° for BTAC, respectively. However, theoretical calculation results prove the conformational stabilization energy changes little, less than 1.5 kcal/mol, as dihedral angle changes from 50° to 100°. Hydrogen bonding is sufficient to overcome the energy required for this conformational change. Therefore, both BTBE and BTAC can produce water stimulation response luminescence behavior. This stimulating response behavior of BTBE and BTAC can be applied to the preparation of water writable film materials.

Microscopic insight to specificity of metal ion cofactor in DNA cleavage by restriction endonuclease EcoRV.

Restriction endonucleases protect bacterial cells against bacteriophage infection by cleaving the incoming foreign DNA into fragments. In presence of Mg2+ ions, EcoRV is able to cleave the DNA but not in presence of Ca2+ , although the protein binds to DNA in presence of both metal ions. We make an attempt to understand this difference using conformational thermodynamics. We calculate the changes in conformational free energy and entropy of conformational degrees of freedom, like DNA base pair steps and dihedral angles of protein residues in Mg2+ (A)-EcoRV-DNA complex compared to Ca2+ (S)-EcoRV-DNA complex using all-atom molecular dynamics (MD) trajectories of the complexes. We find that despite conformational stability and order in both complexes, the individual degrees of freedom behave differently in the presence of two different metal ions. The base pairs in cleavage region are highly disordered in Ca2+ (S)-EcoRV-DNA compared to Mg2+ (A)-EcoRV-DNA. One of the acidic residues ASP90, coordinating to the metal ion in the vicinity of the cleavage site, is conformationally destabilized and disordered, while basic residue LYS92 gets conformational stability and order in Ca2+ (S) bound complex than in Mg2+ (A) bound complex. The enhanced fluctuations hinder placement of the metal ion in the vicinity of the scissile phosphate of DNA. Similar loss of conformational stability and order in the cleavage region is observed by the replacement of the metal ion. Considering the placement of the metal ion near scissile phosphate as requirement for cleavage action, our results suggest that the changes in conformational stability and order of the base pair steps and the protein residues lead to cofactor sensitivity of the enzyme. Our method based on fluctuations of microscopic conformational variables can be applied to understand enzyme activities in other protein-DNA systems.

Large scale Full QM-MD investigation of small peptides and insulin adsorption on ideal and defective TiO2 (1 0 0) surfaces. Influence of peptide size on interfacial bonds

Large biomolecule interaction with oxide surface has attracted a lot of attention because it drives behavior of implanted devices in the living body. To investigate the role of TiO2 surface structure on a large polypeptide (insulin) adsorption, we use a homemade mixed Molecular Dynamics-Full large scale Quantum Mechanics code. A specific re-parameterized (Ti) and globally convergent NDDO method fitted on high level ab initio method (coupled cluster CCSD(T) and DFT) allows us to safely describe the electronic structure of the whole insulin-TiO2 surface system (up to 4000 atoms). Looking specifically at carboxylate residues, we demonstrate in this work that specific interfacial bonds are obtained from the insulin/TiO2 system that are not observed in the case of smaller peptides (tripeptides, insulin segment chains with different configurations). We also demonstrate that a large part of the adsorption energy is compensated by insulin conformational energy changes and surface defects enhanced this trend. Large slab dimensions allow us to take into account surface defects that are actually beyond ab initio capabilities owing to size effect. These results highlight the influence of the surface structure on the conformation and therefore of the possible inactivity of an adsorbed polypeptides.

Molecular Dynamics Study on Mechanism of Preformed Particle Gel Transporting Through Nanopores: Deformation and Dehydration

Understanding the translocation mechanism of preformed particle gel (PPG) through the nanoporous medium is crucial for gel treatment during enhanced oil recovery. On the basis of nonequilibrium molecular dynamics simulation, the translocation process of PPG in silica nanopores consisting of two different diameters was investigated. During the simulation, an external pulling force was applied to PPG representing the injection pressure. The simulation results suggest that a synergetic deformation and dehydration of PPG occurs during the translocation from the wide side into the narrow side. The energy barrier of the translocation process mainly result from the conformational energy change of PPG (mainly from the angle bend and dihedral torsion) and the dissociation energy barrier between PPG’s hydrophilic groups and water. Furthermore, the nanopore size has a crucial impact on the translocation mechanism of PPG, not only the degree of the deformation and dehydration near the entrance, but also the transloca...

Analysis of the conformational profiles of fenamates shows route towards novel, higher accuracy, force-fields for pharmaceuticals.

In traditional molecular mechanics force fields, intramolecular non-bonded interactions are modelled as intermolecular interactions, and the form of the torsion potential is based on the conformational profiles of small organic molecules. We investigate how a separate model for the intramolecular forces in pharmaceuticals could be more realistic by analysing the low barrier to rotation of the phenyl ring in the fenamates (substituted N-phenyl-aminobenzoic acids), that results in a wide range of observed angles in the numerous fenamate crystal structures. Although the conformational energy changes by significantly less than 10 kJ mol(-1) for a complete rotation of the phenyl ring for fenamic acid, the barrier is only small because of small correlated changes in the other bond and torsion angles. The maxima for conformations where the two aromatic rings approach coplanarity arise from steric repulsion, but the maxima when the two rings are approximately perpendicular arise from a combination of an electronic effect and intramolecular dispersion. Representing the ab initio conformational energy profiles as a cosine series alone is ineffective; however, combining a cos 2ξ term to represent the electronic barrier with an intramolecular atom-atom exp-6 term for all atom pairs separated by three or more bonds (1-4 interactions) provides a very effective representation. Thus we propose a new, physically motivated, generic analytical model of conformational energy, which could be combined with an intermolecular model to form more accurate force-fields for modelling the condensed phases of pharmaceutical-like organic molecules.

Endotherm just above glass transition in uniaxially drawn poly(lactic acid)s films with various d-isomer contents

The endothermic heat just above glass transition for the drawn poly(lactic acid)s (PLAs) films with four different d-isomer contents (1, 4, 10, and 20 mol%: named as PLA1, PLA4, PLA10, and PLA20) was observed on differential scanning calorimetry (DSC) heating scan. The amount of endothermic heat increases with increasing the draw ratio, which means that the endotherm is undoubtedly caused by stretching the PLAs films. The endotherm is clearly seen in the drawn films of amorphous PLAs (PLA10 and PLA20). In the crystalline PLA4, the endothermic heat decreases with increasing crystallinity. Hence, it is considered that the endotherm is closely related to some events occurring in the amorphous phase of the drawn PLAs films. In order to verify an association between endothermic event and macroscopic shrinking deformation, two types of dimensional constraints during DSC measurement, which are effective in restraining the sample shrinkage, were imposed on a drawn PLA10 monofilament. The endothermic temperature of PLA10 with draw ratio of 4 moves from 62 °C for a free filament to 67 °C for an ends-fixed one. For a filament ends-fixed and very tightly rolled up with aluminum sheet, a sharp endothermic peak does not appear. Instead, a very broad endothermic curve ranging from 90 °C to 172 °C shows up, suggesting that the stretched chains in a filament with severe dimensional constraint relax slowly toward isotropic state over broad range of temperature. This result implies that the heat-absorption is contemporaneous with the macroscopic shrinkage of drawn filament. It was also visually confirmed that a drawn sample is shrunk above the endothermic peak. The conformational energy change during macroscopic shrinking deformation, determined by using Raman spectroscopic method, is comparable to the endothermic heat. Hence, the main origin of endothermic heat seems to be the conformational energy change during shrinking deformation.

A phenomenological relationship between molecular geometry change and conformational energy change

A linear correlation is established between the change in the axial/equatorial conformational energy difference and the change in the molecular geometry transformation during conformational inversion in substituted six-membered ring systems, namely in the 1-substituted cyclohexane/silacyclohexane, cyclohexane/ N-substituted piperidine and 1-substituted silacyclohexane/ P-substituted phosphorinane compound families, and for the analogous gauche/anti conformational isomerism in 1-substituted propanes/1-silapropanes. The nuclear repulsion energy parameterizes the molecular geometry, and changes in the conformational energy between the related compound families are linearly correlated with the changes in the nuclear repulsion energy difference based on DFT (B3LYP, M06-2X), G3B3, and CBS-QB3 calculations. This correlation reproduces the sometimes remarkable contrast between the conformational behavior of analogous compounds, e.g., the lack of a general equatorial preference in silacyclohexanes.

Single Amino Acid Substitutions in Lattice Proteins Using Statistical Mechanical Model for Protein Folding

The folding of lattice proteins with single amino acid substitutions was studied using a statistical mechanical model for protein folding. All possible single amino acid substitutions were analyzed for two different native conformations, and two amino acid sequences foldable to the given native conformation were considered for each native conformation. First, the transition temperature change Δ T m (ξ i ) with the conformational energy change Δ E (ξ i ) caused by the substitution of the amino acid residue type ξ i at the i -th residue was examined. Although both Δ E (ξ i ) and Δ T m (ξ i ) strongly depend on the amino acid sequence (as a result, these two changes for the two proteins with different amino acid sequences foldable to the same native conformation differ considerably from each other), it is indicated that the correlations between Δ E (ξ i ) and Δ T m (ξ i ) for the given residue i of the two proteins are mainly determined by their native conformations and are less dependent on their amino acid...

Conformational Transitions in RNA Single Uridine and Adenosine Bulge Structures: A Molecular Dynamics Free Energy Simulation Study

Extra unmatched nucleotides (single base bulges) are common structural motifs in folded RNA molecules and can participate in RNA-ligand binding and RNA tertiary structure formation. Often these processes are associated with conformational transitions in the bulge region such as flipping out of the bulge base from an intrahelical stacked toward a looped out state. Knowledge of the flexibility of bulge structures and energetics of conformational transitions is an important prerequisite to better understand the function of this RNA motif. Molecular dynamics simulations were performed on single uridine and adenosine bulge nucleotides at the center of eight basepair RNA molecules and indicated larger flexibility of the bulge bases compared to basepaired regions. The umbrella sampling method was applied to study the bulge base looping out process and accompanying conformational and free energy changes. Looping out toward the major groove resulted in partial disruption of adjacent basepairs and was found to be less favorable compared to looping out toward the minor groove. For both uridine and adenosine bulges, a positive free energy change for full looping out was obtained which was ∼1.5 kcal mol −1 higher in the case of the adenosine compared to the uridine bulge system. The simulations also indicated stable partially looped out states with the bulge bases located in the RNA minor groove and forming base triples with 5′-neighboring basepairs. In the case of the uridine bulge this state was more stable than the intrahelical stacked bulge structure. Induced looping out toward the minor groove involved crossing of an energy barrier of ∼3.5 kcal mol −1 before reaching the base triple state. A continuum solvent analysis of intermediate bulge states indicated that electrostatic interactions stabilize looped out and base triple states, whereas van der Waals interactions and nonpolar contributions favor the stacked bulge conformation.

Scaling of Network Segment Dimensions in Hyperelastic Composites

The change in elastomer tensile moduli, as formulated in the Gaussian statistical theory of rubber elasticity, with deformation, is considered both experimentally and theoretically. Gum elastomers of different structures and corresponding materials filled with carbon black, as reinforcing filler, are investigated experimentally. For all materials considered, the same scaling pattern with negative and low slope for small deformations, and positive and higher slope for large deformations is obtained, indicating two distinct mechanisms of elastic response. Most pronounced is the similarity of small deformation responses for filled materials. Considering the modulus as an elastic energy density gradient dependent on structure changes with deformation, and interpreting the changes for small deformations in terms of conformational energy change, the fractal dimension of a new type is formulated. It describes the decrease in elastomer network connectivity with deformations, which is discussed in terms of conformon dynamics. Possibilities of application of Faynman's path integral method and statistical method of random walk to the lattice are considered for the conformon, as well.

Molecular Modeling, Design, and Synthesis of Less Lipophilic Derivatives of 3‐(4‐Tetradecyloxybenzyl)‐4H‐1,2,4‐oxadiazol‐5‐one (PMS1062) Specific for Group II Enzyme

Abstract3‐(4‐Tetradecyloxybenzyl)‐4H‐1,2,4‐oxadiazol‐5‐one (PMS1062 or I) can probably act as a PLA2‐II inhibitor on the acute inflammation model, but its highly lipophilic character could prevent it from being biodistributed effectively. In this work, based on a molecular modeling study, we have proposed a model that may provide compounds retaining both anti‐PLA2 activity and specificity while becoming active per os. Moreover, molecular dynamics and energy minimization enabled us to characterize the lowest‐energy complexes of each derivative. Energy balances taking account of the conformational energy changes of both partners, along with the drug–protein interaction, were performed, and were further completed by single‐point computations of the contributions of solvation/desolvation to the binding. The ordering of the resulting energy balances was found to be fully consistent with the experimentally ascertained ordering of affinities inferred from the IC50 values. The essential role of an indole group partaking in cation–π and hydrophobic interactions, together with the CaII‐chelating oxadiazolone ring, was highlighted for the best binding compound. (© Wiley‐VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2005)

Bimodal Complexations of Steroids with Cyclodextrins by a Flexible Docking Algorithm

A flexible docking algorithm was developed for studying the inclusion complexes of cyclodextrins with steroids in aqueous solution by an optimization method and an empirical function. The function is used to estimate the binding free energy including intermolecular interaction energy, the conformational energy change, and the solvation energy. The bimodal complexations of twelve steroids in β- and γ-CD cavities were studied by the algorithm. For the two orientations of the guests in the cavity, the possible binding regions were investigated, and the lowest energies for the inclusion complexes in the binding regions were obtained. The stability constant for each orientation was estimated from the optimized energy components by a quantitative model. Therefore, the preferential orientations of the guests were found out from the results finally.

Differential recognition of resveratrol isomers by the human estrogen receptor-alpha: molecular dynamics evidence for stereoselective ligand binding.

Resveratrol (RSVL) is a phytoestrogen that occurs naturally in two forms (trans- (E) and cis- (Z)). We have conducted molecular dynamics (MD) studies to differentially characterize the estrogen receptor-alpha (ER-alpha) binding profiles of RSVL stereoisomers. Favorable orientations for RSVL isomers at the ER-alpha pocket were first inferred from (1) alignment with pharmacophoric elements of the pure ER-alpha agonists estradiol (E2) and (2) assessment of ligand recognition by the ER-alpha binding domain. Subsequently, these orientations for RSVL isomers were subjected to MD analyses versus E2. A 100-picosecond MD simulation revealed that E2 contributed four stable hydrogen bonds with the key ER-alpha pocket residue: Arg394, Glu353, His524, and Leu525. Further, E2 displayed favorable binding energy, conformational energy change (DeltaE), and movement of the binding pocket residues (RMSd). Compared to E2, (E)-RSVL lacked a hydrogen bond (HB) with His524 but formed three additional bonds with Gly521, Phe404, and Met343 of the ER-alpha pocket. Further, (E)-RSVL conferred more favorable energy of interaction, less favorable DeltaE, but comparable RMSd values. In contrast, (Z)-RSVL orientations missed hydrogen bonding (HB) with His524 and Leu525, two essential ligand binding residues, and/or produced considerably less favorable-binding energy, -DeltaE, and -RMSd values than did (E)-RSVL. In conclusion, the present study demonstrates the utility of this MD model in distinguishing between RSVL stereoisomers. The weak binding of (Z)-RSVL by the human ER-alpha binding is congruent with its inferior ligand profiles in ER-endowed biological systems. Further, evidence is provided for a considerable variation in the mode of recognition of the mixed agonist/antagonist (E)-RSVL, and the pure agonist E2.

Linear free-energy model description of the conformational stability of uracil-DNA glycosylase inhibitor A thermodynamic characterization of interaction with denaturant and cold denaturation.

The equilibrium unfolding of uracil DNA glycosylase inhibitor (Ugi), a small acidic protein of molecular mass 9474 Da, has been studied by a combination of thermal-induced and guanidine hydrochloride (GdnCl)-induced denaturation. The analysis of the denaturation data provides a measure of the changes in conformational free energy, enthalpy, entropy and heat capacity DeltaCp that accompany the equilibrium unfolding of Ugi over a wide range of temperature and GdnCl concentration. The unfolding of Ugi is a simple two-state, reversible process. The protein undergoes both low-temperature and high-temperature unfolding even in the absence of GdnCl but more so in the presence of denaturant. The data are consistent with the linear free-energy model and with a temperature independent DeltaCp over the large temperature range of unfolding. The small DeltaCp (6.52 kJ.mol-1.K-1) for the unfolding of Ugi, is perhaps a reflection of a relatively small, buried hydrophobic core in the folded form of this small monomeric protein. Despite a relatively low value of DeltaG(H2O), 7.40 kJ.mol-1 at pH 8.3, Ugi displays considerable stability with the temperature of maximum stability being 301.6 K.

A molecular theory of stress–strain relationship of spherulitic materials

A primitive molecular theory for stress–strain relationship of spherulitic polymers is presented based on a consideration of changes in conformational free energy in the tie chains and floating chains located between crystalline lamellae within an ideal spherulite which is assumed to undergo an affine deformation. Numerical stress–strain curves are calculated as a function of temperature, crystallinity, and tie chain fraction.

Local relaxation of polymers in dense media: Cooperative kinematics theory and applications

AbstractCooperative kinematics (CK) theory and its recent applications are presented. CK theory has been developed as an efficient approach for predicting the mechanism of segmental relaxation processes in bulk polymers. The theory aims at determining the most probable changes in atomic coordinates, occurring collectively in response to a given, external or localized, structural perturbation. The basic postulate is the minimization of the energy change involved in the overall conformational motion, which naturally yields the optimal pathway of cooperative relaxation. Attention has been confined here to the collective motions accompanying the rotational transitions of backbone bonds in polyethylene (PE) and polybutadiene (PB). The strong dependence of the mechanism of motions on the geometry of the repeat unit and on chain connectivity is emphasized. The differences in the types of correlated transitions operating in different structures, the effective conformational energy changes triggered by bond rotational jumps, and the correlation lengths for particular bond isomerizations are analyzed. The reorientations of CH bond vectors in cis‐ and trans‐PB are also examined to explain the shorter correlation time of cis units, compared to trans, detected by NMR. A good agreement between various CK predictions and results from molecular dynamics (MD) simulations is obtained. The fact that CK calculations are at least two orders of magnitude faster than MD simulations invites attention to the utility of the CK method as an efficient tool for elucidating the pathway of motion in complex systems.

Chain flattening of spin-cast PMMMA on aluminum mirrors: Influence of polymer tacticity

Polymer tacticity has already been shown to be an influential parameter governing the behavior of polymer solutions and polymer blends, but not for polymer adsorption. However, using PMMA having a racemic fraction (ƒ r) ranging from 0.1 to 0.9, spin-cast on aluminum mirror surfaces, makes it possible to work out configuration differences in the adsorbed layer. Reflectance infra-red spectroscopy has been used to evaluate the fraction of surface bonded carbonyl groups (ƒ ab CO) and local conformations of both main and side chain. The ƒ ab CO value is 0.1 for highly syndiotactic PMMA and reaches 0.7 for mainly isotactic PMMA. This latter very high value of ƒ ab CO can only be explained by chain flattening resulting from a distortion from its Isotropic state. This distortion may be due to both strong interactions that may exist between PMMA and the aluminium substrate, and also to the spin-cast process that may lead to chain straightening and flattening. The assumption of conformational energy changes of both backbone and side chain is confirmed by changes in the FT-IR Av 2(1245 cm −1) Av 1(1265–1275 cm −1 ) ratio. Ellipsometric spectroscopy has provided information on the global conformation of adsorbed chains by precise thickness measurements. Thus, thickness ( h) increases for diluted solutions linearly from 10 to 70 A as the average syndiotactic sequence length ( n s ) increases. However, IR and ellipsometric results tend to prove that isotactic PMMA may adsorb on the aluminum surface in a more flattened way with longer chains than atactic and syndiotactic chains. This can be explained by the ability of chain segmental rearrangements ( meso tg state) that may allow isotactic PMMA to favor the establishment of interfacial acid-base bonds while the syndiotactic PMMA local stiffness of the tt state does not. The influence of the chain entropy in solution is also discussed as an important parameter.

Trans-1,2-Cyclohexanedicarboxylic acid derivatives as pH-trigger for conformationally controlled crowns

Conversion of trans-1,2-cyclohexanedicarboxylic acid derivatives into dianions under the action of strong bases leads to dramatic conformational changes: a conformer with diaxial position of carboxylate groups becomes predominant. Thus the trans-1,2-cyclohexanedicarboxylic acid moiety can be used for pH-induced conformational switching. The conformational energy changes upon protonation amount to 10 kJ/mol.

Relative Contributions of Coupled Rotations and Small-Amplitude Torsions to Conformational Relaxation in Polymers

Local dynamics of polyethylene and 1,4-trans-polybutadiene chains are analyzed by the cooperative kinematics approach. The method includes the effects of environmental friction and the conformational energy changes involved in bond rotational motions. A given bond is rotated by 120° and the response of the surrounding bonds along the chain, which are necessary for localizing the motion, are analyzed. The conformational responses are classified into two sets, one exhibiting a coupled rotation of another bond, i.e. involving a rotational barrier crossing, and the other accommodated by collective small-amplitude torsions (librational) of several bonds in the neighborhood of the rotating bond. Coupled rotations are shown to increase significantly with increasing environmental frictional resistance. Conversely, librational motions are dominant for localization in less viscous environments. An important finding is that, for polyethylene, the subset of transitions in which the relaxation is achieved by torsional...