Potential of genetic algorithms in protein folding and protein engineering simulations

Genetic algorithms are very efficient search mechanisms whichmutate, recombine and select amongst tentative solutions toa problem until a near optimal one is achieved. We introducethem as a new tool to study proteins. The identification andmotivation for different fitness functions is discussed. Theevolution of the zinc finger sequence motif from a random startis modelled. User specified changes of the repressor structurewere simulated and critical sites and exchanges for mutagenesisidentified. Vast conformational spaces are efficiently searchedas illustrated by the ab initio folding of a model protein ofa four ß strand bundle. The genetic algorithm simulationwhich mimicked important folding constraints as overall hydrophobicpackaging and a propensity of the betaphilic residues for transpositions achieved a unique fold. Cooperativity in the ßstrand regions and a length of 3–5 for the interconnectingloops was critical. Specific interaction sites were considerablyless effective in driving the fold.     

The investigation of the effects of counterions in protein dynamics simulations

Molecular simulations able to exactly represent solvated chargedproteins are helpful in understanding protein dynamics, structureand function. In the present study we have used two differentstarting structures of papain (a typical, stable, globular proteinof intermediate net charge) and different modeling proceduresto evaluate some effects of counterions in simulations. A numberof configurations have been generated and relaxed for each systemby various combinations of constrained simulated annealing andmolecular dynamics procedures, using the AMBER force field.The analysis of trajectories shows that the simulations of solvatedproteins are moderately sensitive to the presence of counterions.However, this sensitivity is highly dependent on the startingmodel and different procedures of equilibration used. The neutralizedsystems tend to evince smaller root mean square deviations regardlessof the system investigated and the simulation procedure used.The results of parameterized fitting of the simulated structuresto the crystallographic data, giving quantitative measure ofthe total charge influence on the stability of various elementsof the secondary structure, revealed a clear scatter of differentreactions of various systems' secondary structures to counterionsaddition: some systems apparently were stabilized when neutralized,while the others were not. Thus, one cannot unequivocally state,despite consideration of specific simulation conditions, whetherprotein secondary structures are more stable when they haveneutralized charges. This suggests that caution should be takenwhen claiming the stabilizing effect of counterions in simulationsother than those involving small, unstable polypeptides or highlycharged proteins.     

Molecular dynamics simulations of the protein unfolding/folding reaction

All-atom molecular dynamics simulations of proteins in solvent are now able to realistically map the protein-unfolding pathway. The agreement with experiments probing both folding and unfolding suggests that these simulated unfolding events also shed light on folding. The simulations have produced detailed models of protein folding transition, intermediate, and denatured states that are in both qualitative and quantitative agreement with experiment. The various studies presented here highlight how such simulations both complement and extend experiment.     

Molecular dynamics simulations of the whey protein {beta}-lactoglobulin

Molecular dynamics simulations have been used to model the motionsand conformational behavior of the whey protein bovine ß-lactoglobulin.Simulations were performed for the protein by itself and complexedto a single retinol ligand located in a putative interior bindingpocket. In the absence of the retinol ligand, the backbone loopsaround the opening of this ulterior pocket shifted inward topartially close off this cavity, similar to the shifts observedin previously reported molecular dynamics simulations of theuncomplexed form of the homologous retinol binding protein.The protein complexed with retinol does not exhibit the sameconformational shifts. Conformational changes of this type couldserve as a recognition signal allowing in vivo discriminationbetween the free and retinol complexed forms of the 3-lactoglobulinmolecule. The unusual bending of the single a-helix observedin the simulations of retinol binding protein were not observedin the present calculations     

高转速轴用多唇油封及其模具结构设计

对多唇密封圈双向密封的性能、结构和特点及硫化模结构设计中的相关技术要点进行了总结阐述。     

Molecular dynamics simulations as a tool for improving protein stability

Haloalkane dehalogenase (DhlA) was used as a model protein toexplore the possibility to use molecular dynamics (MD) simulationsas a tool to identify flexible regions in proteins that canserve as a target for stability enhancement by introductionof a disulfide bond. DhlA consists of two domains: an     

Atomistic molecular simulations of structure and dynamics of crosslinked epoxy resin

Many excellent thermal and mechanical performances of cured epoxy resin products can be related to their specific network structure. In this work, a typical crosslinked epoxy resin was investigated using detailed molecular dynamics (MD) simulations, in a wide temperature range from 250 K to 600 K. A general constant-NPT MD procedure widely used for linear polymers failed to identify the glass transition temperature (T_g) of this crosslinked polymer. This can be attributed to the bigger difference in the time scales and cooling rates between the experiments and simulations, and specially to the highly crosslinked infinite network feature. However, by adopting experimental densities appropriate for the corresponding temperatures, some important structural and dynamic features both below and above T_g were revealed using constant-NVT MD simulations. The polymer system exhibited more local structural features in case of below T_g than above T_g, as suggested by some typical radial distribution functions and torsion angle distributions. Non-bond energy, not any other energy components in the used COMPASS forcefield, played the most important role in glass transition. An abrupt change occurring in the vicinity of T_g was also observed in the plots of the mean squared displacements (MSDs) of the crosslinks against the temperature, indicating the great importance of crosslinks to glass transition. Rotational dynamics of some bonds in epoxy segments were also investigated, which exhibited great diversity along the chains between crosslinks. The reorientation functions of these bond vectors at higher temperatures can be well fitted by Kohlrausch-Williams-Watts (KWW) function.     

On the relevance of accounting for the evolution of the fractal dimension in aerosol process simulations

A population balance model is presented, which tracks particle growth in the gas phase and accounts for simultaneous agglomeration and sintering: Simulations reveal the evolution of the full distribution of a volume equivalent diameter and, amongst others, the evolution of the agglomerate collision diameter, a mean primary particle size and the number of primary particles per agglomerate. Furthermore, assuming fractal behaviour of the growing agglomerate particles—for the first time—a model for the evolution of a mean value of the fractal dimension based on physical and process parameters is proposed and incorporated into the simulation model. PARSIVAL, a commercial solver for integro-differential equations is employed to solve the equations involved. It is based on a generalised finite-element scheme with self-adaptive grid- and order construction. Calculations are performed to validate the model against monodisperse and sectional models published in literature for the exemplary case of Si production. The results are in good agreement if the same simplifying assumptions are made. However, results obtained from the new model for both—isothermal and non-isothermal process conditions—clearly show that it is important to consider the changing fractal dimension in many cases.     

Atomistic simulations of the structure and thermodynamic properties of poly(1,2-vinyl-butadiene) surfaces

Computer simulations play an important role in the design of new polymers and in the prediction of the properties of existing polymers. Atomistic modeling of amorphous poly(1,2-vinyl butadiene) using molecular mechanics and molecular dynamics simulations was carried out in three-dimensionally periodic and effective two-dimensionally periodic condensed phases. Sets of sample structures of two different periodicity (box edge lengths of 23.982 and 30.042 Å) were generated in order to explore the structural and energetic aspects as a function of the simulation cell size. The calculated surface energy for poly(1,2-vinyl-butadiene) compares very well with the experimental value reported in literature. The equilibrium structure of the films shows an interior region of mass density reasonably close to the value in the bulk state and an outer surface layer of approximately 20 Å across which the density falls rapidly but smoothly to zero at the outer limit of the free surface. The overall characteristics of the atomistic simulation approach is found to be similar to those presented in previous investigations for flexible polymers. In order to create the surface from the bulk state, energetic changes as a result of changes in the states of torsions and bond angles are favored, and these are opposite to the changes in the energies originating from non-bonded interactions. The dominant molecular energetic contribution to the formation of the surface is from dispersion forces (van der Waals).     

Parallel algorithm for numerical self-consistent field theory simulations of block copolymer structure

An efficient algorithm is presented for numerically evaluating a self-consistent field theoretic (SCFT) model of block copolymer structure. This algorithm is implemented on a distributed memory parallel cluster in order to solve the SCFT equations on large computational grids. Simulation results are presented for a two-component molten mixture of a symmetric ABA triblock copolymer with an A homopolymer. These results illustrate a case in which simulating a large system is required to resolve features with a wide range of length scales.     

Bubble removal in rotational molding

Closed form solutions have been obtained for bubble dissolution in typical polymer melts encountered in rotational molding. The solutions are in excellent agreement with experimental data available in the literature. Using these solutions, it is shown that under typical rotational molding conditions the polymer melts may be almost saturated. As a result, bubble shrinkage occurs over long periods. Depending on the degree of saturation, surface tension may contribute substantially to the concentration gradient that drives bubble shrinkage. It is also shown that a pressure increase imposed on a nearly saturated polymer melt leads to a steep concentration gradient at the bubble/melt interface that can cause extremely fast bubble shrinkage. Applied to the rotational molding process, such a pressure increase can result in substantial cycle‐time shortening through elimination (or reduction) of the currently used excessive heating. A further benefit may be that additional resins, which at present cannot be used because of oxidation at sustained high‐temperatures, can become available to the rotational molding industry. Under the under‐saturated conditions created by a pressure increase, the effect of surface tension on the rate of bubble shrinkage is negligible.     

3D Dislocation structure evolution in strontium titanate: Spherical indentation experiments and MD simulations

In the present work, the dislocation structure evolution around and underneath the spherical indentations in (001) oriented single crystalline strontium titanate (STO) was revealed by using an etch‐pit technique and molecular dynamics (MD) simulations. The 3D defect structure at various length scales and subsurface depths was resolved with the help of a sequential polishing, etching, and imaging technique. This analysis, combined with load‐displacement data, shows that the incipient plasticity (manifested as sudden indenter displacement bursts) is strongly influenced by preexisting dislocations. In the early stage of plastic deformation, the dislocation pile‐ups are all aligned in 〈100〉 directions, lying on {110}₄₅ planes, inclined at 45° to the (001) surface. At higher mean contact pressure and larger indentation depth, however, dislocation pile‐ups along 〈110〉 directions appear, lying on {110}₉₀ planes, perpendicular to the (100) surface. MD simulations confirm the glide plane nature and provide further insights into the dislocation formation mechanisms by tracing the evolution of the complete dislocation line network as function of indentation depth.     

Molecular simulations of the structure and thermal transport of high alumina aluminosilicate molten core glass fiber

The atomistic structure and phonon transport in aluminosilicate glasses made via an interfacial mixing model of the Molten Core process were studied using molecular dynamics simulations. In the simulations, silica glass was brought in contact with different size alumina crystals (to afford core glasses with 4, 18, 24, 29, and 41 mole% alumina concentrations), followed by a melt‐quench process to enable mixing of the phases. The atomistic structure of the resulting glasses and radius of gyration calculations of resultant Al‐O‐Al connected clusters were evaluated. Variation in the 1‐dimensional thermal transport in each glass was also determined and showed that increased alumina concentration in the glasses resulted in increased transport of thermal energy. Results of the structural analyses showed a double peak in the Al‐Al pair distribution function, with the short‐distance peak indicative of edge‐sharing Al‐O‐Al‐O bonding and a longer distance peak of Al‐O‐Al bonding that is not indicative of edge‐sharing structures. The ratio of the first Al‐Al peak to the second Al‐Al peak varied inversely with the thermal transport behavior. An increased radius of gyration of Al‐O‐Al connectivity occurred with increasing alumina concentration, providing a mechanism for the increased thermal transport. Nanosegregation was also observed. Interconnectivity between Al ions created isolated Al‐O‐Al bonded clusters at low alumina concentrations with lower thermal transport than the high alumina glasses, whereas the latter showed a percolated network of Al‐O‐Al bonds that increased thermal transport.     

Evolution and physics in comparative protein structure modeling

From a physical perspective, the native structure of a protein is a consequence of physical forces acting on the protein and solvent atoms during the folding process. From a biological perspective, the native structure of proteins is a result of evolution over millions of years. Correspondingly, there are two types of protein structure prediction methods, de novo prediction and comparative modeling. We review comparative protein structure modeling and discuss the incorporation of physical considerations into the modeling process. A good starting point for achieving this aim is provided by comparative modeling by satisfaction of spatial restraints. Incorporation of physical considerations is illustrated by an inclusion of solvation effects into the modeling of loops.     

On the structure of macroreticular styrene-divinylbenzene copolymers

The influence of the removal of various diluents, pore forming agents from the porous styrene-ethylstyrene-acrylonitrile-divinylbenzene copolymers on the structure of the matrix was investigated by several methods. The most advantageous pathway to preserve the initial structural edifice of the porous networks performed in the presence of solvating diluents consisted in the removal of the inert media with methanol as it was noticed from the experimental data. If the steam treatment is applied, the collapse effect takes place and the anion exchangers prepared from such matrices exchange/adsorb less dye stuff by comparison with ones formed from beads treated with methanol, because the pore size was changed. It was also noticed that the porous copolymers performed in the presence of the solvating diluents (mixtures of solvatings and precipitants) swell very well in methanol though it is a precipitating medium for the polystyrenic macromolecular chains.     

On the structure of a nickel-molybdenum-alumina catalyst

TEM pictures show that the MoS₂ of a sulfided NiMo-alumina catalyst preferentially agglomerates at steps of the alumina support. Catalyst samples aged during direct coal liquefaction either 2 or 26 days show single MoS₂ layers at steps of the support, and the length of the agglomerates is about the same in the two catalysts. The data is not consistent with models for the catalyst structure that include multi-layers of MoS₂.     

On the internal structure of pressure-sensitive adhesives

The internal structure of pressure-sensitive adhesives was studied using electron microscopy and measurements of mechanical loss, tensile modulus, viscosity, stress relaxation, and critical surface tension. The adhesives were blends of natural rubber and the pentaerythritol ester of hydrogenated rosin. Compositions containing up to 40 wt-% resin are homogeneous mixtures. The temperature dispersion of mechanical loss shows a single peak, and the peak value remains almost constant. When the resin concentration exceeds 40 wt-%, phase separation occurs. The disperse phase is resin containing a small amount of rubber. Two peaks, or a peak and a shoulder, appear in the temperature–loss peak curves. It is postulated that one of the peaks corresponds to the phase in which resin is uniformly dispersed in the rubber and the other peak corresponds to the resin phase which contains a small amount of rubber. Evidence for homogeneity in compositions containing 40 wt-% or less resin and of heterogeneity at higher concentrations of resin was also obtained from the electron microscope observations. The relationships between the internal structure of pressure-sensitive adhesives and viscosity, Young's modulus, the relaxation spectrum, tack, and critical surface tension are discussed.