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Biomedical subjects

A E Mark

Publications and source records attributed to A E Mark.

At least 19 recordsLinked to original sources
PubMed2007

Elevated body mass index and mortality risk in the elderly.

The purpose of this report was to perform a systematic review and meta-analysis of the studies examining the impact of an elevated body mass index (BMI) on mortality risk in elderly (> or =65 years) men and women. A variance-based method of meta-analysis was used to summarize the relationships from available studies. The summary relative risk of all-cause mortality from the 26 analyses that included a risk estimate for a BMI within the overweight range was 1.00 (95% confidence intervals, 0.97-1.03). The summary relative risk of all-cause mortality for the 28 analyses that included a risk estimate for a BMI within the obese range was 1.10 (1.06-1.13). These calculations indicate that a BMI in the overweight range is not associated with a significantly increased risk of mortality in the elderly, while a BMI in the moderately obese range is only associated with a modest increase in mortality risk.

Aged↗
PubMed2006

Separate and combined influence of body mass index and waist circumference on arthritis and knee osteoarthritis.

OBJECTIVE: To determine if the combination of body mass index (BMI) and waist circumference (WC) explains an additional component of arthritis and knee osteoarthritis risk than is accounted for by either anthropometric measure alone. DESIGN: Cross-sectional study. PARTICIPANTS: Participants were part of the Third National Health and Nutrition Examination Survey, a representative sample of Americans conducted from 1988 to 1994. The arthritis analyses included 15 570 participants aged 18 years and older. The knee osteoarthritis analyses included 2323 participants aged 60 years and older. Body mass index and WC were measured in all participants and classified into sex-specific tertiles. OUTCOME MEASURES: Arthritis (determined by self-report) and knee osteoarthritis (determined by radiograph). RESULTS: Independent of sex, the likelihood of arthritis and knee osteoarthritis increased in a graded fashion when moving from the lowest to highest BMI tertile and when moving from the lowest to highest WC tertile (Ptrend < 0.01). In the next phase of analyses, subjects were divided into WC tertiles within each of the BMI tertiles. Within the lowest BMI tertile, the likelihood of arthritis and knee osteoarthritis was not different in the lowest, middle and highest WC tertiles (P > 0.1). Within the middle BMI tertile, the middle and high WC tertiles were more likely to have knee osteoarthritis compared to the lowest WC tertile (P < 0.05). Within the highest BMI tertile, the highest WC tertile was more likely to have arthritis and knee osteoarthritis compared to the lowest WC tertile (P < 0.05). CONCLUSIONS: Both BMI and WC were strong predictors of arthritis and knee osteoarthritis. When a categorical approach was used for BMI and WC, similar to that in the clinical setting, independent effects of these anthropometric variables were observed.

Adult↗
PubMed2002

Molecular dynamics simulations of mixed micelles modeling human bile.

Extensive molecular dynamics (MD) simulations of binary systems of phospholipids and bile salts, a model for human bile, have been performed. Recent progress in hardware and software development allows simulation of the spontaneous aggregation of the constituents into small mixed micelles, in agreement with experimental observations. The MD simulations reveal the structure of these micelles at atomic detail. The phospholipids are packed radially with their headgroups at the surface and the hydrophobic tails pointing toward the micellar center. The bile salts act as wedges between the phospholipid headgroups, with their hydrophilic sides exposed to the aqueous environment. The structure of the micelles strongly resembles the previously proposed radial shell model. Simulations including small fractions of cholesterol reveal how cholesterol is solubilized inside these mixed micelles without changing their overall structure.

Bile↗
PubMed2001

Investigation of the mechanism of domain closure in citrate synthase by molecular dynamics simulation.

Six, 2 ns molecular dynamics simulations have been performed on the homodimeric enzyme citrate synthase. In three, both monomers were started from the open, unliganded X-ray conformation. In the remaining three, both monomers started from a closed, liganded X-ray conformation, with the ligands removed. Projecting the motion from the simulations onto the experimental domain motion revealed that the free-energy profile is rather flat around the open conformation, with steep sides. The most closed conformations correspond to hinge-bending angles of 12-14 compared to the 20 degrees that occurs upon the binding of oxaloacetate. It is also found that the open, unliganded X-ray conformation is situated at the edge of the steep rise in free energy, although conformations that are about 5 degrees more open were sampled. A rigid-body essential dynamics analysis of the combined open trajectories has shown that domain motions in the direction of the closed X-ray conformation are compatible with the natural domain motion of the unliganded protein, which has just two main degrees of freedom. The simulations starting from the closed conformation suggest a free-energy profile with a small barrier in going from the closed to open conformation. A combined essential dynamics and hinge-bending analysis of a trajectory that spontaneously converts from the closed to open state shows an almost exact correspondence to the experimental transition that occurs upon ligand binding. The simulations support the conclusion from an earlier analysis of the experimental transition that the beta-hairpin acts as a mechanical hinge by attaching the small domain to the large domain through a conserved main-chain hydrogen bond and salt-bridges, and allowing rotation to occur via its two flexible termini. The results point to a mechanism of domain closure in citrate synthase that has analogy to the process of closing a door.

Citrate (si)-Synthase↗
PubMed2001

Free energy barrier estimation of unfolding the alpha-helical surfactant-associated polypeptide C.

Molecular dynamics simulations were conducted to estimate the free energy barrier of unfolding surfactant-associated polypeptide C (SP-C) from an alpha-helical conformation. Experimental studies indicate that while the helical fold of SP-C is thermodynamically stable in phospholipid micelles, it is metastable in a mixed organic solvent of CHCl3/CH3OH/0.1 M HCl at 32:64:5 (v/v/v), in which it undergoes an irreversible transformation to an insoluble aggregate that contains beta-sheet. On the basis of experimental observations, the free energy barrier was estimated to be approximately 100 kJ/mole by applying Eyring's transition state theory to the experimental rate of unfolding [Protein Sci 1998;7:2533-2540]. These studies prompted us to carry out simulations to investigate the unwinding process of two helical turns encompassing residues 25-32 in water and in methanol. The results give an upper bound estimation for the free energy barrier of unfolding of SP-C of approximately 20 kJ/mole. The results suggest a need to reconsider the applicability of a single-mode activated process theory to protein unfolding.

Amino Acid Sequence↗
PubMed2001

Essential dynamics of reversible peptide folding: memory-free conformational dynamics governed by internal hydrogen bonds.

A principal component analysis has been applied on equilibrium simulations of a beta-heptapeptide that shows reversible folding in a methanol solution. The analysis shows that the configurational space contains only three dense sub-states. These states of relatively low free energy correspond to the "native" left-handed helix, a partly helical intermediate, and a hairpin-like structure. The collection of unfolded conformations form a relatively diffuse cloud with little substructure. Internal hydrogen-bonding energies were found to correlate well with the degree of folding. The native helical structure folds from the N terminus; the transition from the major folding intermediate to the native helical structure involves the formation of the two most C-terminal backbone hydrogen bonds. A four-state Markov model was found to describe transition frequencies between the conformational states within error limits, indicating that memory-effects are negligible beyond the nanosecond time-scale. The dominant native state fluctuations were found to be very similar to unfolding motions, suggesting that unfolding pathways can be inferred from fluctuations in the native state. The low-dimensional essential subspace, describing 69% of the collective atomic fluctuations, was found to converge at time-scales of the order of one nanosecond at all temperatures investigated, whereas folding/unfolding takes place at significantly longer time-scales, even above the melting temperature.

Computer Simulation↗
PubMed2001

Entropy calculations on a reversibly folding peptide: changes in solute free energy cannot explain folding behavior.

The configurational entropy of a beta-heptapeptide in solution at four different temperatures is calculated. The contributions of the backbone and of the side-chain atoms to the total peptide entropy are analyzed separately and the effective contribution to the entropy arising from correlations between these terms determined. The correlation between the backbone and side-chain atoms amounts to about 17% and is rather insensitive to the temperature. The correlation of motion within the backbone and within side-chains is much larger and decreases with temperature. As the peptide reversibly folds at higher temperatures, its change in entropy and enthalpy upon folding is analyzed. The change in entropy and enthalpy upon folding of the peptide alone cannot account for the observed change in free energy on folding of the peptide in solution. Enthalpic and entropic contributions of the solvent thus also play a key role. Proteins 2001;43:45-56.

Entropy↗
PubMed2000

On the temperature and pressure dependence of a range of properties of a type of water model commonly used in high-temperature protein unfolding simulations.

Molecular dynamics simulations of protein folding and unfolding are often carried out at temperatures (400-600 K) that are much higher than physiological or room temperature to speed up the (un)folding process. Use of such high temperatures changes both the protein and solvent properties considerably, compared to physiological or room temperature. Water models designed for use in conjunction with biomolecules, such as the simple point charge (SPC) model, have generally been calibrated at room temperature and pressure. To determine the distortive effect of high simulation temperatures on the behavior of such "room temperature" water models, the structural, dynamic, and thermodynamic properties of the much-used SPC water model are investigated in the temperature range from 300 to 500 K. Both constant pressure and constant volume conditions, as used in protein simulations, were analyzed. We found that all properties analyzed change markedly with increasing temperature, but no phase transition in this temperature range was observed.

Calibration↗
PubMed1999

The effect of motional averaging on the calculation of NMR-derived structural properties.

The effect of motional averaging when relating structural properties inferred from nuclear magnetic resonance (NMR) experiments to molecular dynamics simulations of peptides is considered. In particular, the effect of changing populations of conformations, the extent of sampling, and the sampling frequency on the estimation of nuclear Overhauser effect (NOE) inter-proton distances, vicinal (3)J-coupling constants, and chemical shifts are investigated. The analysis is based on 50-ns simulations of a beta-heptapeptide in methanol at 298 K, 340 K, 350 K, and 360 K. This peptide undergoes reversible folding and samples a significant proportion of the available conformational space during the simulations, with at 298 K being predominantly folded and at 360 K being predominantly unfolded. The work highlights the fact that when motional averaging is included, NMR data has only limited capacity to distinguish between a single fully folded peptide conformation and various mixtures of folded and unfolded conformations. Proteins 1999;36:542-555.

Computer Simulation↗
PubMed1999

Folding-unfolding thermodynamics of a beta-heptapeptide from equilibrium simulations.

The thermodynamics of folding and unfolding of a beta-heptapeptide in methanol solution has been studied at four different temperatures, 298 K, 340 K, 350 K, and 360 K, by molecular dynamics simulation. At each of these temperatures, the 50-ns simulations were sufficient to generate an equilibrium distribution between a relatively small number of conformations (approximately 10(2)), showing that, even above the melting temperature (approximately 340 K), the peptide does not randomly sample conformational space. The free energy of folding and the free energy difference between pairs of conformations have been calculated from their relative populations. The experimentally determined folded conformation at 298 K, a left-handed 3(1)-helix, is at each of the four temperatures the predominant conformation, with its probability and average lifetime decreasing with increasing temperature. The most common intermediates of folding and unfolding are also the same at the four temperatures. Paths and rates of interconversion between different conformations have been determined. It has been found that folding can occur through multiple pathways, not necessarily downhill in free energy, although the final step involves a reduced number of intermediates.

Models, Molecular↗
PubMed1998

Reversible peptide folding in solution by molecular dynamics simulation.

Long-standing questions on how peptides fold are addressed by the simulation at different temperatures of the reversible folding of a peptide in solution in atomic detail. Molecular dynamics simulations correctly predict the structure that is thermodynamically stable at 298 K, irrespective of the initial peptide conformation. The rate of folding and the free energy of folding at different temperatures are estimated. Although the conformational space potentially accessible to the peptide is extremely large, very few conformers (10(1) to 10(2)) are significantly populated at 20 K above the melting temperature. This implies that the search problem in peptide (or even protein) folding is surmountable using dynamics simulations.

Computer Simulation↗
PubMed1998

Molecular dynamics simulations of peptide fragments from hen lysozyme: insight into non-native protein conformations.

Molecular dynamics simulations of four peptides taken from the hen lysozyme sequence have been used to generate models for non-native protein conformations. Comparisons between the different peptides and with experimental data for denatured lysozyme and peptide fragments provides insight into the characteristics of the conformational ensembles populated in these non-native states and the dependence of their structural features on the amino acid sequence. For the denatured conformers populated local contacts dominate in determining the properties observed in the trajectories, all four peptides showing similar characteristics. These include a significant increase in the number of main-chain O(i)-NH(i+2) hydrogen bonds and hydrogen bonds involving side-chain groups, this increase compensating to a large extent for the loss of hydrogen bonds involved in helical or beta-sheet secondary structure in the native fold, and the generation of a population of collapsed states with local clusterings of hydrophobic groups. The hydrophobic clusters enable at least partial burial of many side-chains exposed by the loss of tertiary contacts on denaturation and provide models that may explain the experimentally observed protection of amides from hydrogen exchange and the existence of residual secondary structure in non-native species of lysozyme. The results suggest that this approach has an important role to play in aiding the interpretation of experimental data for conformationally disordered non-native states of proteins.

Animals↗
PubMed1997

Solvent structure at a hydrophobic protein surface.

The impact of an extensive, uniform and hydrophobic protein surface on the behavior of the surrounding solvent is investigated. In particular, focus is placed on the possible enhancement of the structure of water at the interface, one model for the hydrophobic effect. Solvent residence times and radial distribution functions are analyzed around three types of atomic sites (methyl, polar, and positively charged sites) in 1 ns molecular dynamics simulations of the alpha-helical polypeptide SP-C in water, in methanol and in chloroform. For comparison, water residence times at positively and negatively charged sites are obtained from a simulation of a highly charged alpha-helical polypeptide from the protein titin in water. In the simulations the structure of water is not enhanced at the hydrophobic protein surface, but instead is disrupted and devoid of positional correlation beyond the first solvation sphere. Comparing solvents of different polarity, no clear trend toward the most polar solvent being more ordered is found. In addition, comparison of the water residence times at nonpolar, polar, positively charged, or negatively charged sites on the surface of SP-C or titin does not reveal pronounced or definite differences. It is shown, however, that the local environment may considerably affect solvent residence times. The implications of this work for the interpretation of the hydrophobic effect are discussed.

Amino Acid Sequence↗
PubMed1995

Fluctuation and cross-correlation analysis of protein motions observed in nanosecond molecular dynamics simulations.

Nanosecond molecular dynamics simulations of bovine pancreatic trypsin inhibitor and lysozyme in water are analyzed in terms of backbone atomic positional fluctuations and dynamical cross-correlations. It is found that although the molecular systems are stable, B-factors calculated over a time period as long as 500 ps are not representative for the motions within the proteins. This is especially true for the most mobile residues. On a nanosecond time-scale, the B-factors calculated from the simulations of the proteins in solution are considerably larger than those obtained by structure refinement of the proteins in crystals, based on X-ray data. The time evolution of the atomic fluctuations shows that for large portions of the proteins under study, atomic positional fluctuations are not yet converged after a nanosecond. Cross-correlations do not converge faster than the fluctuations themselves. Most display very erratic behavior if the sampling covers less than about 200 ps. It is also shown that inclusion of mobile atoms into the procedure used to remove rigid-body motion from the simulation can lead to spurious correlations between the motions of the atoms at the surface of the protein.

Animals↗
PubMed1995

Comparison of MD simulations and NMR experiments for hen lysozyme. Analysis of local fluctuations, cooperative motions, and global changes.

Three 1000 ps molecular dynamics simulations of hen lysozyme have been compared with a range of experimental NMR parameters in order to gain insight into the dynamical properties of the protein and to assess the significance of the motional events observed in the simulations. The simulations, one in vacuum and two in water, were used to estimate interproton distances (for comparison with NOE data), 3JHN alpha and 3J alpha beta coupling constants and 1H-15N order parameters. Comparison of these values with experimental data, particularly NOEs, enabled force field-induced changes to the structure during the simulations to be recognized. It has been shown, however, that these changes can be largely eliminated by slight modifications to the force field. Using a simulation performed in water with this modified force field, it has been found that 1H-15N order parameters calculated for side chain groups in particular correlate well with experimental values and reflect the substantial dependence of these motional properties on the environment, particularly surface exposure, in which the side chain is found. In this case, the simulation then provides models for the motional processes giving rise to the observed experimental data. The results indicate that the order parameter values reflect primarily the number of torsion angles about which rotameric interchange occurs. In addition to local motions, the two different domains of lysozyme have been found to behave differently in the simulations. Possible implications of these differences for the interpretation of unfolding simulations and experimental observations of folding intermediates for lysozyme are discussed.

Animals↗
PubMed1995

Investigation of protein unfolding and stability by computer simulation.

Structural, dynamic and energetic properties of proteins in solution can be studied in atomic detail by molecular dynamics computer simulation. Protein unfolding can be caused by a variety of driving forces induced in different ways: increased temperature or pressure, change of solvent composition, or protein amino acid mutation. The stability and unfolding of four different proteins (bovine pancreatic trypsin inhibitor, hen egg white lysozyme, the surfactant protein C and the DNA-binding domain of the 434 repressor) have been studied by applying the afore-mentioned driving forces and also to some artificial forces. The results give a picture of protein (in)stability and possible unfolding pathways, and are compared to experimental data where possible.

Amino Acid Sequence↗
PubMed1995

The effect of environment on the stability of an integral membrane helix: molecular dynamics simulations of surfactant protein C in chloroform, methanol and water.

A series of three molecular dynamics simulations at 300 K in explicit solvent environments of chloroform, methanol and water has been performed on the pulmonary surfactant lipoprotein, SP-C, comprising several consecutive valine residues in order to investigate the stability of the alpha-helical conformation. Two additional simulations were performed on truncated SP-C with a five-residue N-terminal deletion at 300 K and 500 K in water, the high temperature run in order to increase the rate of peptide denaturation. Indications of destabilization appear in chloroform during 1 ns while the SP-C alpha-helix is remarkably stable during 1 ns in methanol and water. In particular the polyvalyl part comprising residues Val15 to Val21 remains intact even at elevated temperature, and the valines do not disrupt the alpha-helical conformation. The valyl-rotamer sampling is partly restricted. Unfolding takes place successively along the primary sequence starting from the C-terminal end. Factors affecting polypeptide stability in molecular dynamics simulations are addressed. The intrinsic helix-forming tendency of valine residues and its dependence on the sequence context, and the role of the solvent environment in stabilizing or destabilizing an alpha-helical fold, are discussed.

Amino Acid Sequence↗