... Numerical Methods for Stochastic Molecular Dynamics -- 8. ...
Interdisciplinary Applied Mathematics, ISSN 0939-6047 39
1st edition XXII, 443 stran : ilustrace ; 24 cm
- MeSH
- Mathematics MeSH
- Molecular Dynamics Simulation MeSH
- Publication type
- Monograph MeSH
- Conspectus
- Matematika
- NML Fields
- přírodní vědy
Given by χ torsional angles, rotamers describe the side-chain conformations of amino acid residues in a protein based on the rotational isomers (hence the word rotamer). Constructed rotamer libraries, based on either protein crystal structures or dynamics studies, are the tools for classifying rotamers (torsional angles) in a way that reflect their frequency in nature. Rotamer libraries are routinely used in structure modeling and evaluation. In this perspective article, we would like to encourage researchers to apply rotamer analyses beyond their traditional use. Molecular dynamics (MD) of proteins highlight the in silico behavior of molecules in solution and thus can identify favorable side-chain conformations. In this article, we used simple computational tools to study rotamer dynamics (RD) in MD simulations. First, we isolated each frame in the MD trajectories in separate Protein Data Bank files via the cpptraj module in AMBER. Then, we extracted torsional angles via the Bio3D module in R language. The classification of torsional angles was also done in R according to the penultimate rotamer library. RD analysis is useful for various applications such as protein folding, study of rotamer-rotamer relationship in protein-protein interaction, real-time correlation between secondary structures and rotamers, study of flexibility of side chains in binding site for molecular docking preparations, use of RD as guide in functional analysis and study of structural changes caused by mutations, providing parameters for improving coarse-grained MD accuracy and speed, and many others. Major challenges facing RD to emerge as a new scientific field involve the validation of results via easy, inexpensive wet-lab methods. This realm is yet to be explored.
The article reviews the application of biomolecular simulation methods to understand the structure, dynamics and interactions of nucleic acids with a focus on explicit solvent molecular dynamics simulations of guanine quadruplex (G-DNA and G-RNA) molecules. While primarily dealing with these exciting and highly relevant four-stranded systems, where recent and past simulations have provided several interesting results and novel insight into G-DNA structure, the review provides some general perspectives on the applicability of the simulation techniques to nucleic acids.
- MeSH
- DNA chemistry MeSH
- G-Quadruplexes * MeSH
- Guanine chemistry MeSH
- Nucleic Acid Conformation MeSH
- Ligands MeSH
- RNA chemistry MeSH
- Solvents chemistry MeSH
- Molecular Dynamics Simulation * MeSH
- Telomere chemistry MeSH
- Hydrogen Bonding MeSH
- Publication type
- Journal Article MeSH
- Research Support, Non-U.S. Gov't MeSH
- Review MeSH
- Research Support, N.I.H., Extramural MeSH
- Research Support, U.S. Gov't, Non-P.H.S. MeSH
Intense pulsed electric fields are known to act at the cell membrane level and are already being exploited in biomedical and biotechnological applications. However, it is not clear if electric pulses within biomedically-attainable parameters could directly influence intra-cellular components such as cytoskeletal proteins. If so, a molecular mechanism of action could be uncovered for therapeutic applications of such electric fields. To help clarify this question, we first identified that a tubulin heterodimer is a natural biological target for intense electric fields due to its exceptional electric properties and crucial roles played in cell division. Using molecular dynamics simulations, we then demonstrated that an intense - yet experimentally attainable - electric field of nanosecond duration can affect the bβ-tubulin's C-terminus conformations and also influence local electrostatic properties at the GTPase as well as the binding sites of major tubulin drugs site. Our results suggest that intense nanosecond electric pulses could be used for physical modulation of microtubule dynamics. Since a nanosecond pulsed electric field can penetrate the tissues and cellular membranes due to its broadband spectrum, our results are also potentially significant for the development of new therapeutic protocols.
- MeSH
- Electric Stimulation * methods MeSH
- Humans MeSH
- Molecular Dynamics Simulation * MeSH
- Static Electricity MeSH
- Tubulin physiology MeSH
- Binding Sites MeSH
- Check Tag
- Humans MeSH
- Publication type
- Journal Article MeSH
- Research Support, Non-U.S. Gov't MeSH
Kinesin is a biological molecular nanomotor which converts chemical energy into mechanical work. To fulfill various nanotechnological tasks in engineered environments, the function of biological molecular motors can be altered by artificial chemical modifications. The drawback of this approach is the necessity of designing and creating a new motor construct for every new task. We propose that intense nanosecond-scale pulsed electric field could modify the function of nanomotors. To explore this hypothesis, we performed molecular dynamics simulation of a kinesin motor domain docked on a subunit of its microtubule track - a single tubulin heterodimer. In the simulation, we exposed the kinesin motor domain to intense (100 MV/m) electric field up to 30 ns. We found that both the magnitude and angle of the kinesin dipole moment are affected. Furthermore, we found that the electric field affects contact surface area between kinesin and tubulin, the structure and dynamics of the functionally important kinesin segments, including microtubule binding motifs as well as nucleotide hydrolysis site which power the nanomotor. These findings indicate that external intense nanosecond-scale electric field could alter kinesin behavior. Our results contribute to developing novel electromagnetic methods for modulating the function of biomolecular matter at the nanoscale.
With both catalytic and genetic functions, ribonucleic acid (RNA) is perhaps the most pluripotent chemical species in molecular biology, and its functions are intimately linked to its structure and dynamics. Computer simulations, and in particular atomistic molecular dynamics (MD), allow structural dynamics of biomolecular systems to be investigated with unprecedented temporal and spatial resolution. We here provide a comprehensive overview of the fast-developing field of MD simulations of RNA molecules. We begin with an in-depth, evaluatory coverage of the most fundamental methodological challenges that set the basis for the future development of the field, in particular, the current developments and inherent physical limitations of the atomistic force fields and the recent advances in a broad spectrum of enhanced sampling methods. We also survey the closely related field of coarse-grained modeling of RNA systems. After dealing with the methodological aspects, we provide an exhaustive overview of the available RNA simulation literature, ranging from studies of the smallest RNA oligonucleotides to investigations of the entire ribosome. Our review encompasses tetranucleotides, tetraloops, a number of small RNA motifs, A-helix RNA, kissing-loop complexes, the TAR RNA element, the decoding center and other important regions of the ribosome, as well as assorted others systems. Extended sections are devoted to RNA-ion interactions, ribozymes, riboswitches, and protein/RNA complexes. Our overview is written for as broad of an audience as possible, aiming to provide a much-needed interdisciplinary bridge between computation and experiment, together with a perspective on the future of the field.
A recent study described an allosteric effect in which the binding of a protein to DNA is influenced by another protein bound nearby. The effect shows a periodicity of ∼10 basepairs and decays with increasing protein-protein distance. As a mechanistic explanation, the authors reported a similar periodic, decaying pattern of the correlation coefficient between major groove widths inferred from a shorter molecular dynamics simulation. Here we show that in a state-of-the-art, microsecond-long simulation of the same DNA sequence, the periodicity of the correlation coefficient is not observed. To study the problem further, we extend an earlier mechanical model of DNA allostery based on constrained minimization of effective quadratic deformation energy of the DNA. We demonstrate that, if the constraints mimicking the bound proteins are properly applied, the periodicity in the binding energy is indeed recovered.
Abstract Aromatic stacking of nucleic acid bases is one of the key players in determining the structure and dynamics of nucleic acids. The arrangement of nucleic acid bases with extensive overlap of their aromatic rings gave rise to numerous often contradictory suggestions about the physical origins of stacking and the possible role of delocalized electrons in stacked aromatic π systems, leading to some confusion about the issue. The recent advance of computer hardware and software finally allowed the application of state of the art quantum-mechanical approaches with inclusion of electron correlation effects to study aromatic base stacking, now providing an ultimitate qualitative description of the phenomenon. Base stacking is determined by an interplay of the three most commonly encountered molecular interactions: dispersion attraction, electrostatic interaction, and short-range repulsion. Unusual (aromatic- stacking specific) energy contributions were in fact not evidenced and are not necessary to describe stacking. The currently used simple empirical potential form, relying on atom-centered constant point charges and Lennard-Jones van der Waals terms, is entirely able to reproduce the essential features of base stacking. Thus, we can conclude that base stacking is in principle one of the best described interactions in current molecular modeling and it allows to study base stacking in DNA using large-scale classical molecular dynamics simulations. Neglect of cooperativity of stacking appears to be the most serious approximation of the currently used force field form. This review summarizes recent developments in the field. It is written for an audience that is not necessarily expert in computational quantum chemistry and follows up on our previous contribution (Sponer et. al., J. Biomol. Struct. Dyn. 14, 117, (1997)). First, the applied methodology, its accuracy, and the physical nature of base stacking is briefly overviewed, including a comment on the accuracy of other molecular orbital methods and force fields. Then, base stacking is contrasted with hydrogen bonding, the other dominant force in nucleic acid structure. The sequence dependence and cooperativity of base stacking is commented on, and finally a brief introduction into recent progress in large-scale molecular dynamics simulations of nucleic acids is provided. Using four stranded DNA assemblies as an example, we demonstrate the efficacy of current molecular dynamics techniques that utilize refined and verified force fields in the study of stacking in nucleic acid molecules.
Ab initio and molecular simulation methods were used in calculations of the neutral individual betulin molecule, and molecular simulations were used to optimize the betulin molecule immersed in various amounts of water. Individual betulin was optimized in different force fields to find the one exhibiting best agreement with ab initio calculations obtained in the Gaussian03 program. Dihedral torsions of active groups of betulin were determined for both procedures, and related calculated structures were compared successfully. The selected force field was used for subsequent optimization of betulin in a water environment, and a conformational search was performed using quench molecular dynamics. The total energies of betulin and its interactions in water bulk were calculated, and the influence of water on betulin structure was investigated.
