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PubMed1992

Rotamer interconversion and its influence on the fluorescence decay of tyrosine: a molecular dynamics study.

To test the hypothesis of charge-transfer quenching between an electrophile in the alanyl sidechain (carbonyl carbon or protonated amino group) and the excited aromatic phenol-subunit, which leads to a bi-exponential fluorescence decay of tyrosine in acidic aqueous solution, we investigated the dynamics of this amino acid and of the peptide Gly-Tyr-Gly in vacuo and in water with classical molecular dynamics (MD) and with stochastic dynamics (SD) computer simulation. The proposed low-frequency of interconversions between sidechain rotamers on a fluorescence time-scale could not be confirmed. Instead, frequent transitions for both, chi 1 and chi 2, dihedrals were observed. Simulating a low pH situation (protonated carboxylate group) did not significantly affect the transition frequency. Rotamer interconversions in the peptide Gly-Tyr-Gly, though significantly less, were also observed although the fluorescence decay of this compound could be described by a uni-modal lifetime distribution centered at 0.8 ns. The results obtained from simulations in vacuo and in solution were critically compared with those of stochastic simulations. We found the stochastic simulation in a better agreement to full MD (water explicitly included), which is highly time consuming, whereas the in vacuo simulations clearly deviated from both. We conclude from our results that, since the rotamers do frequently interconvert within the fluorescence lifetime of tyrosine, their contribution to the non-exponential fluorescence decay should be negligible.

Computer Simulation↗
PubMed2003

A molecular dynamics method for calculating molecular volume changes appropriate for biomolecular simulation.

Photothermal methods permit measurement of molecular volume changes of solvated molecules over nanosecond timescales. Such experiments are an important tool in investigating complex biophysical phenomena including identifying transient species in solution. Developing a microscopic understanding of the origin of volume changes in the condensed phase is needed to complement the experimental measurements. A molecular dynamics (MD) method exploiting available simulation methodology is demonstrated here that both mimics experimental measurements and provides microscopic resolution to the thermodynamic measurements. To calculate thermodynamic volume changes over time, isothermal-isobaric (NPT) MD is performed on a solution for a chosen length of time and the volume of the system is thus established. A further simulation is then performed by "plucking" out a solute molecule of interest to determine the volume of the system in its absence. The difference between these volumes is the thermodynamic volume of the solute molecule. NPT MD allows the volume of the system to fluctuate over time and this results in a statistical uncertainty in volumes that are calculated. It is found in the systems investigated here that simulations lasting a few nanoseconds can discern volume changes of approximately 1.0 ml/mole. This precision is comparable to that achieved empirically, making the experimental and theoretical techniques synergistic. The technique is demonstrated here on model systems including neat water, both charged and neutral aqueous methane, and an aqueous beta-sheet peptide.

Algorithms↗
PubMed1984

[Mathematical simulation of the blood coagulation system].

The Blood coagulation system was converted to a mathematical model which was described using differential equations. The calculated output patterns of the mathematical model against various input stimulations were compared with results of in vitro assay. The simulated results of (1) Hemophilia A, (2) anticoagulation effect of antithrombin III and (3) anticoagulation effect of heparin corresponded to the results of in vitro assay and clinical reports. However, the simulated result of (4) anticoagulation effect of synthesized arginine derivative No. 805 (MD-805) did not correspond to the results of in vitro assay. Therefore, a new series simulation of MD-805 was done, supposing that MD-805 had an inhibitory activity not only on coagulation factor IIa but also VIIa. The new simulation pattern closely resembled the results of in vitro assay. From these facts, it was theoretically indicated that MD-805 also has an inhibitory activity on VIIa.

Adult↗
PubMed2005

Molecular dynamics with the united-residue model of polypeptide chains. II. Langevin and Berendsen-bath dynamics and tests on model alpha-helical systems.

The implementation of molecular dynamics (MD) with our physics-based protein united-residue (UNRES) force field, described in the accompanying paper, was extended to Langevin dynamics. The equations of motion are integrated by using a simplified stochastic velocity Verlet algorithm. To compare the results to those with all-atom simulations with implicit solvent in which no explicit stochastic and friction forces are present, we alternatively introduced the Berendsen thermostat. Test simulations on the Ala(10) polypeptide demonstrated that the average kinetic energy is stable with about a 5 fs time step. To determine the correspondence between the UNRES time step and the time step of all-atom molecular dynamics, all-atom simulations with the AMBER 99 force field and explicit solvent and also with implicit solvent taken into account within the framework of the generalized Born/surface area (GBSA) model were carried out on the unblocked Ala(10) polypeptide. We found that the UNRES time scale is 4 times longer than that of all-atom MD simulations because the degrees of freedom corresponding to the fastest motions in UNRES are averaged out. When the reduction of the computational cost for evaluation of the UNRES energy function is also taken into account, UNRES (with hydration included implicitly in the side chain-side chain interaction potential) offers about at least a 4000-fold speed up of computations relative to all-atom simulations with explicit solvent and at least a 65-fold speed up relative to all-atom simulations with implicit solvent. To carry out an initial full-blown test of the UNRES/MD approach, we ran Berendsen-bath and Langevin dynamics simulations of the 46-residue B-domain of staphylococcal protein A. We were able to determine the folding temperature at which all trajectories converged to nativelike structures with both approaches. For comparison, we carried out ab initio folding simulations of this protein at the AMBER 99/GBSA level. The average CPU time for folding protein A by UNRES molecular dynamics was 30 min with a single Alpha processor, compared to about 152 h for all-atom simulations with implicit solvent. It can be concluded that the UNRES/MD approach will enable us to carry out microsecond and, possibly, millisecond simulations of protein folding and, consequently, of the folding process of proteins in real time.

Algorithms↗
PubMed2002

Mesoscopic dynamics of colloids simulated with dissipative particle dynamics and fluid particle model.

We report results of numerical simulations of complex fluids, using a combination of discrete-particle methods. Our molecular modeling repertoire comprises three simulation techniques: molecular dynamics (MD), dissipative particle dynamics (DPD), and the fluid particle model (FPM). This type of model can depict multi-resolution molecular structures found in complex fluids ranging from single micelle, colloidal crystals, large-scale colloidal aggregates up to the mesoscale processes of hydrodynamical instabilities in the bulk of colloidal suspensions. We can simulate different colloidal structures in which the colloidal beds are of comparable size to the solvent particles. This undertaking is accomplished with a two-level discrete particle model consisting of the MD paradigm with a Lennard-Jones (L-J) type potential for defining the colloidal particle system and DPD or FPM for modeling the solvent. We observe the spontaneous emergence of spherical or rod-like micelles and their crystallization in stable hexagonal or worm-like structures, respectively. The ordered arrays obtained by using the particle model are similar to the 2D colloidal crystals observed in laboratory experiments. The micelle shape and its hydrophobic or hydrophilic character depend on the ratio between the scaling factors of the interactions between colloid-colloid to colloid-solvent. Unlike the miscellar arrays, the colloidal aggregates involve the colloid-solvent interactions prescribed by the DPD forces. Different from the assumption of equilibrium growth, the two-level particle model can display much more realistic molecular physics, which allows for the simulation of aggregation for various types of colloids and solvent liquids over a very broad range of conditions. We discuss the potential prospects of combining MD, DPD, and FPM techniques in a single three-level model. Finally, we present results from large-scale simulation of the Rayleigh-Taylor instability and dispersion of colloidal slab in 2D and 3D. Electronic supplementary material to this paper can be obtained by using the Springer LINK server located at http://dx.doi.org/10.1007/s00894-001-0068-3.

Colloids↗
PubMed2004

Peptides and proteins in membranes: what can we learn via computer simulations?

Membrane and membrane-active peptides and proteins play a crucial role in numerous cell processes, such as signaling, ion conductance, fusion, and others. Many of them act as highly specific and efficient drugs or drug targets, and, therefore, attract growing interest of medicinal chemists. Because of experimental difficulties with characterization of their spatial structure and mode of membrane binding, essential attention is given now to molecular modeling techniques. During the last years an important progress has been achieved in molecular dynamics (MD) and Monte Carlo (MC) simulations of peptides and proteins with explicit and/or implicit theoretical models of membranes. The first ones allow atomic-resolution studies of peptides behavior on the membrane-water interfaces. Models with implicit consideration of membrane are of a special interest because of their computational efficiency and ability to account for principal trends in protein-lipid interactions. In this approximation, the bilayer is usually treated as continuum whose properties vary along the membrane thickness, and membrane insertion is simulated using either MC or MD methods. This review surveys recent applications of both types of lipid bilayer models in computer simulations of a wide variety of peptides and proteins with different biological activities. Theoretical background of the membrane models is considered with examples of their applications to biologically relevant problems. The emphasis of the review is made on recent MC and MD computations, on structural and/or functional information, which may be obtained via molecular modeling. The approximations and shortcomings of the models, along with their perspectives in design of new membrane active drugs, are discussed.

Animals↗
PubMed2000

Effect of carbohydrate supplementation on simulated exercise of rugby league referees.

This investigation evaluated the effectiveness of supplementing eight elite rugby league referees with a 6% maltodextrin (Md) solution whilst undertaking a simulated rugby league game. The simulation was based on motion analysis of six rugby league matches. Subjects undertook two trials of repetitive 20-m shuttle activity on an indoor track. During one trial 200 ml of Md was ingested at eight time points and in the other trial a similarly tasting placebo (Pl) was administered. A single-blind, counterbalanced design was employed. The simulation involved subjects performing four, 10-min blocks of shuttle activity before a 10-min break was instigated. Three further 10-min blocks of shuttle activity were also performed before a performance test to volitional exhaustion involving 20-m shuttles at paces varying between 55 and 95% of a pre-determined VO2max was undertaken. Timed 15-m sprints took place during each of the 10-min blocks. The rating of perceived exertion (RPE), and blood glucose and lactate concentrations were also determined throughout. The mean number of shuttles to exhaustion was significantly greater with Md ingestion than with Pl ingestion (57 +/- 19 vs. 43 + 15; p < 0.05), while the mean 15-m sprint times were significantly shorter for the Md than the Pl condition (2.40 +/- 0.09 s vs. 2.51 +/- 0.14 s; p < 0.01). The mean RPE was 5.2% lower during Md than Pl ingestion, the values being significantly different (Md: 12.07 +/- 0.32; Pl: 12.73 +/- 0.28; p < 0.01). Maltodextrin ingestion significantly elevated blood glucose levels compared with placebo (F(1,7) = 18.07: p < 0.01), although no significant differences were apparent for blood lactate levels (F(1,7) = 4.39; p > 0.05). These results highlight the beneficial effects of maltodextrin ingestion on work-rates of rugby league referees in a simulation of a game's activity. The improvement may be related to higher circulating concentrations of blood glucose.

Adult↗
PubMed2005

Application of molecular dynamics simulations to spin-labeled oligonucleotides.

The EPR study of spin labeled macromolecules has provided insight into structural and dynamical properties of DNA, proteins, and related systems. While spin labeling has been useful, it is experimentally difficult to determine if the spin label significantly alters the conformation of the macromolecule to which it is attached. Molecular modeling has proven to be a powerful tool for studying structure and dynamics of biologically important molecules. Here, we have conducted molecular dynamics (MD) studies of spin labeled oligonucleotides (ONs) bearing a five (5sp) or six (6sp) membered ring nitroxide, and the corresponding unmodified ON using the suite of programs contained in Amber 5.0 with the Cornell et al. 94 force field (Cornell, W. D., Cieplak, P., Bayly, C. I., Gould, I. R., Merz, Jr., K. M. Ferguson, D. M., Spellmeyer, D. C., Fox, T., Caldwell, J. W., and Kollman, P. A. A Second Generation Force Field for the Simulation of Proteins and Nucleic Acids. J. Am. Chem. Soc. 117, 5179-5197 (1995)). Quantum mechanical calculations employing the B3LYP method with the standard 6-31G* basis set using Gaussian98 were performed and, together with available crystallographic data for analogous nitroxides, new parameters for the nitrogen, oxygen, nitroxide alpha-carbon, and sp-hybridized carbon atoms have been developed suitable for the Cornell et al. 94 force field. MD simulations on the double-stranded (ds) spin labeled ONs, along with the corresponding unmodified analogues, have been studied over the course of 4 ns and conformational properties of all ONs are described based on the analysis of the trajectories. The spin labels were found to alter the global conformation of the ONs to which they were attached to accommodate the spin labels. The major changes include widening the major groove, decreasing helical twist, and more negative X-displacement of the base pairs. The magnitude of the effect was dependent on the specific structure of the spin label. Average and 'most representative' structures derived from the molecular dynamics simulations correlate with the experimental data on the spin labeled ONs.

Computer Simulation↗
PubMed2006

Acquisition of basic fiberoptic intubation skills with a virtual reality airway simulator.

STUDY OBJECTIVE: To test the hypothesis that a virtual reality (VR) airway simulator (the AccuTouch Virtual Reality Bronchsocopy Simulator; Immersion Medical, Gaithersburg, MD) can be used to teach residents basic fiberoptic intubation (FOI) skills effectively. DESIGN: Observational study. SETTING: University anesthesiology department. INTERVENTION: Supervised training was done using a VR airway simulator. MEASUREMENTS: Time to intubation before and after a 4-day training period using an adult VR FOI scenario and time to intubation using a fresh human cadaver two weeks after the training experience were measured. MAIN RESULTS: Residents were able to significantly improve time to intubation in the VR scenario (114 vs 75 seconds; P = 0.001). Novices differed from experienced attending anesthesiologists in time to intubation in the VR scenario, before but not after training (114 vs 79 seconds compared with 75 vs 72 seconds). Novices who had been trained with the simulator performed significantly faster in the cadaver than novices who had not (24 vs 86 seconds; P < 0.001). Furthermore, there was no difference in time to intubation in the cadaver between trained novices and experienced attending anesthesiologists (24 vs 23 seconds; P > 0.05). CONCLUSION: Use of a VR airway simulator enables anesthesia residents to acquire basic FOI skills comparable to those of experienced anesthesiologists in a human cadaver.

Cadaver↗
PubMed1991

Conformational analysis of a IgG1 hinge peptide derivative in solution determined by NMR spectroscopy and refined by restrained molecular dynamics simulations.

The hinge region links the antigen binding Fab part to the constant Fc domain in immunoglobulins. For the hinge peptide derivative [AcThr(OtBu)-Cys-Pro-Pro-Cys-Pro-Ala-ProNH2]2 the assignment of the 1H and 13C resonances was achieved by two-dimensional nmr techniques: total correlation spectroscopy (TOCSY), nuclear Overhauser enhancement spectroscopy (NOESY), rotating frame nuclear Overhauser enhancement spectroscopy (ROESY), heteronuclear multiple quantum coherence (HMQC) transfer, and a HSQC (modified Overbodenhausen experiment) with high resolution in F1, which was several times folded in F1 but still phase correctable. Conformational relevant parameters (78 nuclear Overhauser effect distance restraints, 3JHH for prochiral assignments, temperature gradients) were determined by nmr and served as input data for molecular dynamics (MD) structure refinement. A simulated model compound corresponding to the [Cys-Pro-Pro-Cys]2 core elongated by the peptide chains in the Fab and Fc direction served as a starting structure for the final MD run. The conformation calculated in in vacuo does not agree with the C2 symmetry required from nmr data, but the structure obtained by a water simulation fulfills the requirement. Here the core of the hinge peptide derivative adopts a polyproline II double helix as in the x-ray structure of IgG1. Hence, segments responsible for the internal flexibility are located outside the core as confirmed by the flexibility of the solvent exposed C termini.

Amino Acid Sequence↗
PubMed1992

Conformational regions of Boc-Ala-Aib-Ala-OMe. Sampling with molecular dynamics simulations using time averaging of distance restraints.

The method of time averaging of distance restraints in molecular dynamics simulations is applied to Boc-Ala-Aib-Ala-OMe in order to demonstrate the improved sampling properties of this method compared to conventional distance restraining. Two conformational regions, beta-turn type II and gamma-turn, are seen during MD runs at a simulation temperature of 500 K, while in simulations with conventional distance restraining, no conformational transitions could be observed for temperatures up to 1000 K.

Amino Acid Sequence↗
PubMed2002

Colonoscopy curriculum development and performance-based assessment criteria on a computer-based endoscopy simulator.

OBJECTIVE: Computer-based colonoscopy simulators (CBCS) have been developed and are being introduced into the training environment. The ability of these simulators to replicate the dimensions of patient-based diagnostic colonoscopy is good. However, the benefit of simulators to either learners or their patients has not yet been established. We describe a process by which a CBCS curriculum and CBCS-based performance criteria were established for first-year gastroenterology fellows at the Mayo Clinic in Rochester, Minnesota. DESCRIPTION: We used a commercially available CBCS (AccuTouch Endoscopy Simulator, Immersion Medical, Gaithersburg, MD), which consists of a specialized colonoscope that is inserted into a computer-based module with a screen showing the colonic lumen of a virtual patient. A tutorial and six cases of varying complexity are available on the CBCS. Performance variables that are measured by the simulator include the time to complete the procedure, the distance that the scope was advanced, the degree to which the mucosa was adequately visualized, the possible complications such as colonic perforation, and the level of pain experienced by the simulated patient. To begin, we established ideal performance standards by measuring the above variables for ten "expert" faculty colonscopists who completed two cases on the CBCS. Next, we measured CBCS performance standards for five partially trained colonoscopists. Finally, two non-physician gastrointestinal assistants, without prior endoscopic training, were asked to practice on the simulator to determine the time and procedure frequency required to improve their CBCS proficiency. By calculating average performance standards within each of these three groups, we were able to estimate the number of CBCS cases and minimal performance standards for new trainees. Based on the learning curves for novice colonoscopists as well as the performances of partially trained and expert colonoscopists, we speculated that if CBCS training were to be beneficial, the benefit would most likely occur at the early stages of training. The curriculum we developed consists of viewing a one-hour, multimedia tutorial, which describes the procedure and various colonoscopy techniques. This is followed by nine hours of hands-on CBCS experience, during which time the trainee will complete approximately 25 CBCS colonoscopies. Before advancing to live-patient colonoscopies, the trainee must meet certain performance standards on specific CBCS cases. These standards include the ability to view the entire colon in less than 15 minutes with minimal pain and no complications. DISCUSSION: If effective, this new colonoscopy training curriculum should result in improved competency at patient-based colonoscopy, particularly in the early stages of training. To address this question, first-year gastroenterology fellows at Mayo Clinic have been randomized into two groups: (1) a group that experiences a tutorial with hands-on CBCS curriculum and (2) a group that experiences a tutorial only. Their performances at patient-based colonoscopy as well as surveys of patient satisfaction will be measured and analyzed to determine what, if any, benefit is provided by CBCS.

Clinical Competence↗
PubMed2005

Folding and mis-folding of peptides and proteins: insights from molecular simulations.

In this paper, the main achievements and problems of the application of all-atom molecular simulations, with particular attention for Molecular Dynamics (MD), will be critically reviewed. Starting from unfolding simulations, through biased simulations, which require a knowledge of the native state conformation, to folding studies based on the simple knowledge of the protein (or peptide) sequence, the strengths and weaknesses of theoretical approaches to the study of folding and their matching with experimental observations will be discussed. Finally, we will give a critical outlook on the possible developments of this field in the near future.

Computer Simulation↗
PubMedDate not supplied

Membrane-bound ARF1 peptide: interpretation of neutron diffraction data by molecular dynamics simulation methods.

Adenosine diphosphate ribosylation factor-1 (ARF1) is activated by cell membrane binding of a self-folding N-terminal domain. We have previously presented four possible conformations of the membrane bound, human ARF1 N-terminal peptide in planar lipid bilayers of DOPC and DOPG (7:3 molar ratio), determined from lamellar neutron diffraction and circular dichroism data. In this paper we analyse the four possible conformations by molecular dynamics simulations. The aim of these simulations was to use MD to distinguish which of the four possible membrane bound structures was the most likely. The most likely conformation was determined according to the following criteria: (a) location of label positions on the peptide in relation to the bilayer, (b) lowest mean square displacement from the initial structure, (c) lowest system energy, (d) most peptide-lipid headgroup hydrogen bonding, (e) analysis of phi/psi angles of the peptide. These findings demonstrate the application of molecular dynamics simulations to explore neutron diffraction data.

ADP-Ribosylation Factor 1↗
PubMed1994

NMR assignment and conformational analysis of the antigenic capsular polysaccharide from Streptococcus pneumoniae type 9N in aqueous solution.

Complete 1H and 13C NMR assignments, determined by one- and two-dimensional homo- and hetero-nuclear experiments, are reported for the antigenic capsular polysaccharide (CPS) from Streptococcus pneumoniae serotype 9N (S9 in American nomenclature). Distance constraints derived from 1D NOE difference experiments were combined with energy minimisation (simulated annealing) and molecular dynamics (MD) calculations to determine the most favoured conformation of S9 in aqueous solution at 70 degrees C. NOE values simulated for several static conformational models using the NOEMOL program did not correlate well with experimental values, whereas time averaged interproton distances calculated from 500 ps of restrained MD (using the Tropp formalism to account for rapid internal mobility) were in close agreement with experimentally derived distance estimates.

Bacterial Capsules↗
PubMed2006

Amplitudes and directions of internal protein motions from a JAM analysis of 15N relaxation data.

A method has been developed for characterizing dynamic structures of proteins in solution by using nuclear magnetic resonance (NMR) restraints and 15N relaxation data. This method is based on the concept of the jumping-among-minima (JAM) model. In this model we assume that protein dynamics can be described on the basis of conformational substates, and involves intra- and inter-substate motion. A set of substates is created by picking energy-minimized conformations from the conformational space consistent with the geometric NMR restraints. Intra-substate motions, which occur on the timescale of approximately 10 ps, are simulated with molecular dynamics (MD) calculations with force-field energy terms. Statistical weights of the conformational substates are determined to reproduce the NMR relaxation parameters. The refinement procedure consists of four stages: (i) determination of the ensemble of structures that satisfy NMR restraints, (ii) determination of intra-substate fluctuation, (iii) determination of statistical weights of conformational substates to reproduce model-free relaxation parameters, and (iv) analysis of the resulting dynamic structure to determine amplitudes and directions of internal protein motions. This method was employed to investigate structure and dynamics of the adhesion domain of human CD2 (hCD2) in solution. Two major collective modes, whose contributions to atomic mean-square fluctuations are 77.1% in total, are identified by the refinement. The first mode is interpreted as a rigid-body motion of a protein segment consisting of a part of the B--C loop, a part of the F strand, and the F--G loop. Another type of smaller-amplitude mode is indicated for the C'--C'' loop. The motions affect primarily the curvature of the slightly concave counterreceptor-binding site and represent transitions between a concave (closed) and flat (open) binding face. By comparing the ensemble of structures in solution to the complex structure with counterreceptor CD58, we found that these two types of motions resemble the change upon counterreceptor binding.

Models, Molecular↗
PubMed1995

NMR and restrained molecular dynamics study of the three-dimensional solution structure of toxin FS2, a specific blocker of the L-type calcium channel, isolated from black mamba venom.

The three-dimensional solution structure of toxin FS2, a 60-residue polypeptide isolated from the venom of black mamba snake (Dendroaspis polylepis polylepis), has been determined by nuclear magnetic resonance spectroscopy. Using 600 NOE constraints and 55 dihedral angle constraints, a set of 20 structures obtained from distance-geometry calculations was further refined by molecular dynamics calculations using a combined simulated annealing-restrained MD protocol. The resulting 20 conformers, taken to represent the solution structure, give an average rmsd of 1.2 A for their backbone atoms, relative to the average structure. The overall resulting three-fingered structure is similar to those already observed in several postsynaptic neurotoxins, cardiotoxins, and fasciculins, which all share with toxin FS2 the same network of four disulfide bridges. The overall concavity of the molecule, considered as a flat bottomed dish, is oriented toward the C-terminal loop of the molecule. This orientation is similar to that of fasciculins and cardiotoxins but opposite to that of neurotoxins. On the basis of the local rms displacements between the 20 conformers, the structure of the first loop appears to be less well defined in FS2 than in the previously reported neurotoxin structures, but fasciculin 1 shows a similar trend with particularly high temperature factors for this part of the X-ray structure. The concave side which presents most of the positively charged residues is quite similar in FS2 and fasciculin 1. The main difference is shown by the convex side of the third loop, mostly hydrophobic in FS2, in contrast to the pair of negatively charged aspartates in fasciculin 1. This difference could be one of the factors leading to the distinct pharmacological properties-L-type calcium channel blocker for FS2 and cholinesterase inhibitor for fasciculin--observed for these two subgroups of the "angusticeps-type" toxins.

Calcium Channel Blockers↗