A Semiempirical QM/MM Implementation and its Application to the Absorption of Organic Molecules in Zeolites

An intermolecular hybrid semiempirical MO/molecular mechanics technique is described. The model allows polarisation of the quantum mechanical molecule(s), but not of the molecular mechanics part and is shown to be relatively insensitive to the size of the molecular mechanics environment. It has been validated by comparison of calculated and experimental absorption energies of small organic molecules in various zeolites. This validation gives us confidence that the method is also appropriate for experimentally less well characterised problems, such as solvation or ligand/enzyme complexation.     

What are the relations between mechanics, gait parameters, and energetics in terrestrial locomotion?

Are the different energy-conserving mechanics (i.e., pendulum and spring) used in different gaits reflected in differences in energetics and/or stride parameters? The analysis included published data from several species and new data from horses. When changing from pendulum to spring mechanics, there is a change in the slope of metabolic rate (MR) vs. speed in all species, in birds and quadrupeds there is no step increase, and in humans there are conflicting reports. At the trot-gallop transition, where quadrupeds are hypothesized to change from spring mechanics to some combination of spring and pendulum mechanics, there is a change in slope of MR vs. speed in horses but not in other species. Stride frequency (SF) is a logarithmic function of walking speed in all species, a linear function of trotting/running speed, and nearly independent of speed in galloping. In humans and horses there is a discontinuity in SF at the walk-trot (run) transition but not in birds. The slope of time of contact vs. speed does not change with mechanics in most species, but it does in humans. In horses and humans, there is a discontinuity at the walk-trot (run) transition and data for other species do not permit generalization. Duty factor (DF) in humans is greater than 0.5 in walking (pendulum mechanics) and less than 0.5 when running (spring mechanics). However, this is not true in many species that have DF>0.5 at the lowest speeds where they use spring mechanics. When trotting at low speeds, horses use forelimb DF>0.5 and hind limb DF<0.5. Thus, it is confusing to distinguish between walking and running by DF.     

A review of the effects of some endocrinological factors on respiratory mechanics

Context: Endocrinological factors have been recently described to affect respiratory mechanics.

Objective: To review recent literature data, most of all obtained by the end-inflation occlusion method, describing the effects of molecules of endocrinological interest such as endothelin, erythropoietin and renin-angiotensin, on respiratory mechanics parameters.

Methods: The papers considered in this review were found by inserting in Pubmed/Medline the following indexing terms: hormones, endothelin, erythropoietin, angiotensin and respiratory mechanics.

Results: It was found that the above cited molecules, beside their well known physiological main effects, exhibit influences on respiratory mechanics, most of all on the airflow resistance, which was described to be increased by endothelin and angiotensin, and decreased by erythropoietin.

Conclusions: A number of molecules of biological interest exhibit unexpected influences on respiratory mechanics. The clinical effects depend on the consequences of modified inspiratory pressure values the respiratory muscles have to perform for a given breathing pattern.     

Smooth muscle F-actin disassembly and RhoA/Rho-kinase signaling during endotoxin-induced alterations in pulmonary arterial compliance

Endotoxemia is associated with changed pulmonary vascular function with respect to vasoreactivity, endothelial permeability, and activation of inducible nitric oxide synthase II (NOSII). However, whether altered passive arterial wall mechanics contribute to this endotoxin-induced pulmonary vascular dysfunction is still unknown. Therefore, we investigated whether endotoxin affects the passive arterial mechanics and compliance of isolated rat pulmonary arteries. Pulmonary arteries of pentobarbital-anesthetized Wistar rats (n = 55) were isolated and exposed to Escherichia coli endotoxin (50 microg/ml) for 20 h. Endotoxin increased pulmonary artery diameter and compliance (transmural pressure = 13 mmHg) in an endothelium-, Ca2+-, or NOSII-induced NO release-independent manner. Interestingly, the endotoxin-induced alterations in the passive arterial mechanics were accompanied by disassembly of the smooth muscle cell (SMC) F-actin cytoskeleton. Disassembly of F-actin by incubation of control arteries with the cytoskeleton-disrupting agent cytochalasin B or the Rho-kinase inhibitor Y-27632 induced a similar increase in passive arterial diameter and compliance. In contrast, RhoA activation by lysophosphatidic acid prevented the endotoxin-induced alterations in the pulmonary SMC F-actin cytoskeleton and passive mechanics. In conclusion, these findings indicate that disassembly of the SMC F-actin cytoskeleton and RhoA/Rho-kinase signaling act as mediators of endotoxin-induced changes in the pulmonary arterial mechanics. They imply the involvement of F-actin rearrangement and RhoA/Rho-kinase signaling in endotoxemia-induced vascular lung injury.     

Combined quantum and molecular mechanics calculations on metalloproteins

The combination of quantum mechanics and molecular mechanics (QM/MM) methods is one of the most promising approaches to study the structure, function and properties of proteins. The number of QM/MM applications on metalloproteins is steadily increasing, especially studies with density functional methods on redox-active metal centres. Recent developments include new parameterised methods to treat covalent bonds between the quantum and classical systems, methods to obtain free energy from QM/MM results, and the combination of quantum chemistry and protein crystallography.     

Partitioning of respiratory mechanics in mechanically ventilated patients.

In ten mechanically ventilated patients, six with chronic obstructive pulmonary disease (COPD) and four with pulmonary edema, we have partitioned the total respiratory system mechanics into the lung (l) and chest wall (w) mechanics using the esophageal balloon technique together with the airway occlusion technique during constant-flow inflation (J. Appl. Physiol. 58: 1840-1848, 1985). Intrinsic positive end-expiratory pressure (PEEPi) was present in eight patients (range 1.1-9.8 cmH2O) and was due mainly to PEEPi,L (80%), with a minor contribution from PEEPi,w (20%), on the average. The increase in respiratory elastance and resistance was determined mainly by abnormalities in lung elastance and resistance. Chest wall elastance was slightly abnormal (7.3 +/- 2.2 cmH2O/l), and chest wall resistance contributed only 10%, on the average, to the total. The work performed by the ventilator to inflate the lung (WL) averaged 2.04 +/- 0.59 and 1.25 +/- 0.21 J/l in COPD and pulmonary edema patients, respectively, whereas Ww was approximately 0.4 J/l in both groups, i.e., close to normal values. We conclude that, in mechanically ventilated patients, abnormalities in total respiratory system mechanics essentially reflect alterations in lung mechanics. However, abnormalities in chest wall mechanics can be relevant in some COPD patients with a high degree of pulmonary hyperinflation.     

A comparative study of trypsin specificity based on QM/MM molecular dynamics simulation and QM/MM GBSA calculation

Hydrogen bonding and polar interactions play a key role in identification of protein-inhibitor binding specificity. Quantum mechanics/molecular mechanics molecular dynamics (QM/MM MD) simulations combined with DFT and semi-empirical Hamiltonian (AM1d, RM1, PM3, and PM6) methods were performed to study the hydrogen bonding and polar interactions of two inhibitors BEN and BEN1 with trypsin. The results show that the accuracy of treating the hydrogen bonding and polar interactions using QM/MM MD simulation of PM6 can reach the one obtained by the DFT QM/MM MD simulation. Quantum mechanics/molecular mechanics generalized Born surface area (QM/MM-GBSA) method was applied to calculate binding affinities of inhibitors to trypsin and the results suggest that the accuracy of binding affinity prediction can be significantly affected by the accurate treatment of the hydrogen bonding and polar interactions. In addition, the calculated results also reveal the binding specificity of trypsin: (1) the amidinium groups of two inhibitors generate favorable salt bridge interaction with Asp189 and form hydrogen bonding interactions with Ser190 and Gly214, (2) the phenyl of inhibitors can produce favorable van der Waals interactions with the residues His58, Cys191, Gln192, Trp211, Gly212, and Cys215. This systematic and comparative study can provide guidance for the choice of QM/MM MD methods and the designs of new potent inhibitors targeting trypsin.     

Analysis of the Conformational Stability and Activity of Candida antarctica Lipase B in Organic Solvents: INSIGHT FROM MOLECULAR DYNAMICS AND QUANTUM MECHANICS/SIMULATIONS*

The conformational stability and activity of Candida antarctica lipase B (CALB) in the polar and nonpolar organic solvents were investigated by molecular dynamics and quantum mechanics/molecular mechanics simulations. The conformation change of CALB in the polar and nonpolar solvents was examined in two aspects: the overall conformation change of CALB and the conformation change of the active site. The simulation results show that the overall conformation of CALB is stable in the organic solvents. In the nonpolar solvents, the conformation of the active site keeps stable, whereas in the polar solvents, the solvent molecules reach into the active site and interact intensively with the active site. This interaction destroys the hydrogen bonding between Ser¹⁰⁵ and His²²⁴. In the solvents, the activation energy of CALB and that of the active site region were further simulated by quantum mechanics/molecular mechanics simulation. The results indicate that the conformation change in the region of active sites is the main factor that influences the activity of CALB.     

Reciprocal link between cell biomechanics and exocytosis

A cell is able to sense the biomechanical properties of the environment such as the rigidity of the extracellular matrix and adapt its tension via regulation of plasma membrane and underlying actomyosin meshwork properties. The cell's ability to adapt to the changing biomechanical environment is important for cellular homeostasis and also cell dynamics such as cell growth and motility. Membrane trafficking has emerged as an important mechanism to regulate cell biomechanics. In this review, we summarize the current understanding of the role of cell mechanics in exocytosis, and reciprocally, the role of exocytosis in regulating cell mechanics. We also discuss how cell mechanics and membrane trafficking, particularly exocytosis, can work together to regulate cell polarity and motility.      

4-甲酰苯基硼酸对蛋白酶MP的抑制作用及其抑制机制的分子动力学模拟

蛋白酶MP (marine protease)是海洋细菌来源的新型碱性金属蛋白酶,在工业中具有良好的应用前景。本文采用酶动力学方法研究4-甲酰苯基硼酸（4-FPBA）对MP的抑制作用,并结合分子模拟的方法,通过水溶液环境下分子力学 玻尔兹曼泊松表面积（MM-PBSA）和量子力学/分子力学混合方法(QM/MM)对其抑制机制进行了研究。结果表明,4-FPBA对蛋白酶MP的抑制过程属可逆的竞争型抑制,抑制常数Ki为0.57 mmol/L。在4-FPBA与蛋白酶MP的结合过程中,范德瓦尔斯相互作用对于其结合发挥了重要作用。明确了Arg59、Leu151、His190和His196的4个残基为蛋白酶MP中与4-FPBA结合的关键残基。该研究结果将为今后进行蛋白酶MP可逆抑制剂的筛选与设计提供理论基础,以提高其液态稳定性,从而拓宽蛋白酶MP在液体洗涤剂中的高效应用。     

Application of a SCC-DFTB QM/MM approach to the investigation of the catalytic mechanism of fatty acid amide hydrolase

Self-consistent charge density functional tight binding (SCC-DFTB) is a promising method for hybrid quantum mechanics/molecular mechanics (QM/MM) simulations of enzyme-catalyzed reactions. The acylation reaction of fatty acid amide hydrolase (FAAH), a promising drug target, was investigated by applying a SCC-DFTB/CHARMM27 scheme. Calculated potential energy barriers resulted in reasonable agreement with experiments for oleamide (OA) and oleoylmethyl ester (OME) substrates, outperforming previous calculations performed at the PM3/CHARMM22 level. Furthermore, the experimental preference of FAAH in hydrolyzing OA faster than OME was adequately reproduced by calculations. All these findings indicate that the SCC-DFTB/CHARMM27 approach can be successfully applied to mechanistic investigations of FAAH-catalyzed reactions.     

The Fe-CO bond energy in myoglobin: a QM/MM study of the effect of tertiary structure

The Fe-CO bond dissociation energy (BDE) in myoglobin (Mb) has been calculated with B3LYP quantum mechanics/molecular mechanics methods for 22 different Mb conformations, generated from molecular dynamics simulations. Our average BDE of 8.1 kcal/mol agrees well with experiment and shows that Mb weakens the Fe-CO bond by 5.8 kcal/mol; the calculations provide detailed atomistic insight into the origin of this effect. BDEs for Mb conformations with the R carbonmonoxy tertiary structure are on average 2.6 kcal/mol larger than those with the T deoxy tertiary structure, suggesting two functionally distinct allosteric states. This allostery is partly explained by the reduction in distal cavity steric crowding as Mb moves from its T to R tertiary structure.     

Cortical Mechanics and Meiosis II Completion in Mammalian Oocytes Are Mediated by Myosin-II and Ezrin-Radixin-Moesin (ERM) Proteins

Cell division is inherently mechanical, with cell mechanics being a critical determinant governing the cell shape changes that accompany progression through the cell cycle. The mechanical properties of symmetrically dividing mitotic cells have been well characterized, whereas the contribution of cellular mechanics to the strikingly asymmetric divisions of female meiosis is very poorly understood. Progression of the mammalian oocyte through meiosis involves remodeling of the cortex and proper orientation of the meiotic spindle, and thus we hypothesized that cortical tension and stiffness would change through meiotic maturation and fertilization to facilitate and/or direct cellular remodeling. This work shows that tension in mouse oocytes drops about sixfold during meiotic maturation from prophase I to metaphase II and then increases ∼1.6-fold upon fertilization. The metaphase II egg is polarized, with tension differing ∼2.5-fold between the cortex over the meiotic spindle and the opposite cortex, suggesting that meiotic maturation is accompanied by assembly of a cortical domain with stiffer mechanics as part of the process to achieve asymmetric cytokinesis. We further demonstrate that actin, myosin-II, and the ERM (Ezrin/Radixin/Moesin) family of proteins are enriched in complementary cortical domains and mediate cellular mechanics in mammalian eggs. Manipulation of actin, myosin-II, and ERM function alters tension levels and also is associated with dramatic spindle abnormalities with completion of meiosis II after fertilization. Thus, myosin-II and ERM proteins modulate mechanical properties in oocytes, contributing to cell polarity and to completion of meiosis.     

Measurement of myocardial mechanics in mice before and after infarction using multislice displacement-encoded MRI with 3D motion encoding

Cardiac MRI is an accurate, noninvasive modality for assessing the structure and function of the murine heart. In addition to conventional imaging, MRI tissue tracking methods can quantify numerous aspects of myocardial mechanics, including intramyocardial displacement, strain, twist, and torsion. In the present study, we developed and applied a novel pulse sequence based on displacement-encoded imaging using stimulated echoes (DENSE) that achieves multislice coverage, high spatial resolution, and three-dimensional (3D) displacement encoding. With the use of this technique, myocardial mechanics of C57Bl/6 mice were measured at baseline and 1 day after experimental myocardial infarction. At baseline, the mean systolic transmural circumferential strain was -0.14 +/- 0.02 and the mean systolic radial strain was 0.30 +/- 0.05. Changes in circumferential and radial strains from the subepicardium to the subendocardium were detected at baseline (P < 0.05). One day after infarction, significantly reduced 3D displacements and strain were detected in infarcted and noninfarcted myocardium. Infarction also reduced normalized systolic torsion from its baseline value of 1.35 +/- 0.27 degrees /mm (R = 0.99) to 0.07 +/- 0.54 degrees /mm (R = 0.96, P < 0.05). DENSE MRI can assess the 3D myocardial mechanics of the murine heart in <1 h of scan time at 4.7 T and may be applied to studies of myocardial mechanics in genetically engineered mice.     

Effect of severe calorie restriction on the lung in two strains of mice

There is a body of literature in animal models that has suggested the development of emphysema following severe calorie restriction. This has led to the notion of "nutritional emphysema" that might have relevance in COPD patients. There have been few studies, however, that have looked closely at both the mechanics and lung structure in the same animals. In the present work, we examined lung mechanics and histological changes in two strains of mice that have substantial differences in alveolar size, the C57BL/6 and C3H/HeJ strains. We quantified the dynamic elastance and resistance at 2.5 Hz, the quasistatic pressure volume curve, and the alveolar chord lengths in lungs inflated to a lung capacity at 25-30 cm H(2)O. We found that after 2 or 3 wk of calorie restriction to 1/3 their normal diet, the lungs became stiffer with increased resistance. In addition, the lung capacity was also decreased. These mechanical changes were reversed after 2 wk on a normal ad libitum diet. Histology of the postmortem fixed lungs showed no changes in the mean alveolar chord lengths with calorie restriction. Although the baseline mechanics and alveolar size were quantitatively different in the two strains, both strains showed similar qualitative changes during the starvation and refeeding periods. Thus, in two strains of mice with genetically determined differences in alveolar size, neither the mechanics nor the histology show any evidence of emphysema-like changes with this severe caloric insult.     

Conformational effects in enzyme catalysis: reaction via a high energy conformation in fatty acid amide hydrolase

Quantum mechanics/molecular mechanics and molecular dynamics simulations of fatty acid amide hydrolase show that reaction (amide hydrolysis) occurs via a distinct, high energy conformation. This unusual finding has important implications for fatty acid amide hydrolase, a key enzyme in the endocannabinoid system. These results demonstrate the importance of structural fluctuations and the need to include them in the modeling of enzyme reactions. They also show that approaches based simply on studying enzyme-substrate complexes can be misleading for understanding biochemical reactivity.     

A finite element model of myocardial infarction using a composite material approach

Computational models are effective tools to study cardiac mechanics under normal and pathological conditions. They can be used to gain insight into the physiology of the heart under these conditions while they are adaptable to computer assisted patient-specific clinical diagnosis and therapeutic procedures. Realistic cardiac mechanics models incorporate tissue active/passive response in conjunction with hyperelasticity and anisotropy. Conventional formulation of such models leads to mathematically-complex problems usually solved by custom-developed non-linear finite element (FE) codes. With a few exceptions, such codes are not available to the research community. This article describes a computational cardiac mechanics model developed such that it can be implemented using off-the-shelf FE solvers while tissue pathologies can be introduced in the model in a straight-forward manner. The model takes into account myocardial hyperelasticity, anisotropy, and active contraction forces. It follows a composite tissue modeling approach where the cardiac tissue is decomposed into two major parts: background and myofibers. The latter is modelled as rebars under initial stresses mimicking the contraction forces. The model was applied in silico to study the mechanics of infarcted left ventricle (LV) of a canine. End-systolic strain components, ejection fraction, and stress distribution attained using this LV model were compared quantitatively and qualitatively to corresponding data obtained from measurements as well as to other corresponding LV mechanics models. This comparison showed very good agreement.     

Increased surface tension decreases pulmonary capillary volume and compliance.

Increased surface tension is an important component of several respiratory diseases, but its effects on pulmonary capillary mechanics are incompletely understood. We measured capillary volume and specific compliance before and after increasing surface tension with nebulized siloxane in excised dog lungs. The change in surface tension was sufficient to increase lung recoil 5 cm H(2)O at 50% total lung capacity. Increased surface tension decreased both capillary volume and specific compliance. The changes in capillary volume and compliance were greatest at the lung volumes at which the surface tension change was greatest. Near functional residual capacity, capillary volume postsiloxane was approximately 30% of control. Presiloxane capillary specific compliance was approximately 7%/cm H(2)O near functional residual capacity and approximately 2.5%/cm H(2)O near total lung capacity. Postsiloxane capillary-specific compliance was 3%/cm H(2)O, and was independent of lung volume. We conclude that in addition to their well-known effects on lung mechanics, changes in surface tension also have important effects on capillary mechanics. We speculate that these changes may in turn affect ventilation and perfusion, worsen gas exchange, and alter leukocyte sequestration.     

Recent developments in QM/MM methods towards open-boundary multi-scale simulations

Combined quantum mechanics/molecular mechanics (QM/MM) methods have been widely used in multi-scale modelling and simulations of physical, chemical and biological processes in complex environments. In this review, we provide an overview of the recently developed QM/MM algorithms, with emphasis on our works, towards the ultimate goal of establishing an open boundary between the QM and MM subsystems. The open boundary is characterised by on-the-fly exchanges of partial charges and atoms between the QM and MM subsystems, allowing us to focus on the small QM subsystem of primary interest in dynamics simulations. An open-boundary scheme has the promise to the utilisations of small QM subsystems, high-levels of QM theory and long simulation times, which can potentially lead to new insights.     

Multiscale methods for macromolecular simulations

In this article we review the key modeling tools available for simulating biomolecular systems. We consider recent developments and representative applications of mixed quantum mechanics/molecular mechanics (QM/MM), elastic network models (ENMs), coarse-grained molecular dynamics, and grid-based tools for calculating interactions between essentially rigid protein assemblies. We consider how the different length scales can be coupled, both in a sequential fashion (e.g. a coarse-grained or grid model using parameterization from MD simulations), and via concurrent approaches, where the calculations are performed together and together control the progression of the simulation. We suggest how the concurrent coupling approach familiar in the context of QM/MM calculations can be generalized, and describe how this has been done in the CHARMM macromolecular simulation package.