Computer simulations, biopolymers

Using Computer Simulations To Probe the Structure and Dynamics of Biopolymers... 

The use of computer simulations to study internal motions and thermodynamic properties is receiving increased attention. One important use of the method is to provide a more fundamental understanding of the molecular information contained in various kinds of experiments on these complex systems. In the first part of this paper we review recent work in our laboratory concerned with the use of computer simulations for the interpretation of experimental probes of molecular structure and dynamics of proteins and nucleic acids. The interplay between computer simulations and three experimental techniques is emphasized (1) nuclear magnetic resonance relaxation spectroscopy, (2) refinement of macro-molecular x-ray structures, and (3) vibrational spectroscopy. The treatment of solvent effects in biopolymer simulations is a difficult problem. It is not possible to study systematically the effect of solvent conditions, e.g. added salt concentration, on biopolymer properties by means of simulations alone. In the last part of the paper we review a more analytical approach we have developed to study polyelectrolyte properties of solvated biopolymers. The results are compared with computer simulations. 

Vibrational spectroscopy has played a very important role in the development of potential functions for molecular mechanics studies of proteins. Force constants which appear in the energy expressions are heavily parameterized from infrared and Raman studies of small model compounds. One approach to the interpretation of vibrational spectra for biopolymers has been a harmonic analysis whereby spectra are fit by geometry and/or force constant changes. There are a number of reasons for developing other approaches. The consistent force field (CFF) type potentials used in computer simulations are meant to model the motions of the atoms over a large ranee of conformations and, implicitly temperatures, without reparameterization. It is also desirable to develop a formalism for interpreting vibrational spectra which takes into account the variation in the conformations of the chromophore and surroundings which occur due to thermal motions. 

Stem, P. S., M. Chorev, M. Goodman, and A. T. Hagler. 1983. Computer Simulation of the Conformational Properties of Retro-Inverso Peptides. II Ab Initio Study, Spatial Electron Distribution, and Population Analysis of N-Formylglycine Methylamide, N-Formyl N -Acetyldiaminomethane, and N-Methylmalonamide. Biopolymers 22, 1901-1917. 

The computational description of a large biomolecular complex such as the chromatin fiber requires techniques that are difierent from the widely applied molecular dynamics methods used to simulate biopolymers at atomic resolution. 

Theories or computer simulations used to calculate the potential of mean force W(r) are typically based on numerous simplifying assumptions and approximations (de Kruif, 1999 Bratko et al., 2002 Prausnitz, 2003 de Kruif and Tuinier, 2005 Home et al., 2007 Jonsson et al., 2007). Therefore they can provide only a qualitative or, at best, semi-quantitative description of the potential of mean force. Such calculations are nevertheless useful because they can serve as a guide for trends in the factors determining the interactions of both biopolymers and colloidal particles. Thus, an increase in the absolute value of the calculated negative depth of W(r) may be attributed to a predominant type of molecular feature favouring aggregation or self-association. To assist with such a theoretical analysis, expressions for some of the mean force potentials will be presented here in the discussion of specific kinds of interactions occurring between pairs of colloidal particles covered by biopolymers in food colloids. 

Ueda Y, Taketomi H, Go N (1978) Studies on protein folding, unfolding and fluctuations by computer simulation. A three-dimensional lattice model of lysozyme. Biopolymers 17 1531-1548... 

H. Meirovitch, M. Vasquez and H. A. Scheraga, Biopolymers, 26, 651 (1987). Stability of Polypeptide Conformational States as Determined by Computer Simulation of the Free Energy. 

B. R. Brooks, in Supercomputer Research in Chemistry and Chemical Engineering, ACS Symposium Series 353. K. F. Jensen, and D. G. Truhlar, Eds., American Chemical Society, Washington, D.C., 1987, pp. 123-145. Applications of Molecular Dynamics for Structural Analysis of Proteins and Peptides. R. H. Reid, C. A. Hooper, and B. R. Brooks, Biopolymers, 28, 525 (1989). Computer Simulations of a Tumor Surface Octapeptide Epitope. 

H. Meirovitch, S. C. Koerber, J. Riviec, and A. T. Hagler, Biopolymers, 34,815 (1994). Computer Simulation of the Free Energy of Peptides with the Local States Method Analogues of Gonadotropin Releasing Hormone in the Random Coil and Stable States. 

Both experiments and computer simulations demonstrated the fractal character of the mixed floes. The optimal schizophyllan biopolymer/hematite concentration ratio obtained by simulation was smaller than that observed in laboratory experiments. The shift in the optimal dose was mainly attributed to a higher than predicted affinity of hematite for the schizophyllan aggregates present in the initial solution in addition to the presence of a large proportion of chains that did not participate in the flocculation process [12]. 

The development in the last century of a theory of liquid crystalline behaviour and of transfer matrices to understand optical equations, along with the use of computer simulations, has allowed us to understand the theory of these chiral materials. Furthermore, technological advances including electron microscopes have allowed us to unlock the structures of the natural world that create our most vivid materials. We now have the opportunity to capitalise on these in the creation of biocompatible and biomimetic materials using the natural phenomenon of self-assembly observed for abundant and easily processable biopolymers. 

V. S. Pande, I. Baker, J. Chapman, S. P. Elmer, S. Khahq, S. M. Larson, Y. M. Rhee, M. R. Shirts, C. D. Snow, E. J. Sorin, B. Zagrovic (2003) Atomistic protein folding simulations on the submillisecond time scale using worldwide distributed computing. Biopolymers 68, pp. 91-109... 

Large biological molecules, such as superoxide dismutase (SOD), triose phosphate isomerase (TIM), acetylcholinesterase, rhinovirus, bacteriorhodop-sin, antibodies, RNA, and DNA, have become accessible to theoretical study recently as a result of the availability of modern computers and sophisticated theories.Two rapidly emerging areas of interest are the computation of electrostatic interactions using continuum models- - and the simulation of diffusional motion in biopolymers and the diffusional encounters between lig-... 

The experimental studies on biopolymer structures are increasingly supplemented by computational approaches. First, it has to be realized that computation is a sine qua non for experimental structure determination by diffraction methods and NMR spectroscopy themselves. In addition, independent computational studies can provide useful information on structure and dynamics of biopolymers not accessible, at least currently, by experiments. With regard to base poiyads there are three fields that have to be mentioned here primarily quantum-chemical studies of nucleic building blocks, MD simulations of medium-sized nucleic acids and structural bioinformatics. 

Morikami, K., T. Nakai, et al. (1992). Presto(protein engineering simulator)—A vectorized molecular mechanics program for biopolymers. Computers Chemistry 16(3) 243-248. 

Since structures of key biological molecules and of ZnS/MnS nanoparticles are all known, it might be worthwhile to perform a computer modeling of the interactions between biopolymers at the ZnS (MnS) surfaces. The interactions between RNA strands, as well as associations of protein chains and RNA molecules could be modeled at the surface of ZnS templates the results of such simulations might be of great interest for understanding the ZnS-mediated primeval syntheses. 

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