Molecular dynamics Simulation
Dotaz
Zobrazit nápovědu
... Numerical Methods for Stochastic Molecular Dynamics -- 8. ...
Interdisciplinary Applied Mathematics, ISSN 0939-6047 39
1st edition XXII, 443 stran : ilustrace ; 24 cm
- MeSH
- matematika MeSH
- simulace molekulární dynamiky MeSH
- Publikační typ
- monografie MeSH
- Konspekt
- Matematika
- NLK Obory
- přírodní vědy
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.
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 chemie MeSH
- G-kvadruplexy * MeSH
- guanin chemie MeSH
- konformace nukleové kyseliny MeSH
- ligandy MeSH
- RNA chemie MeSH
- rozpouštědla chemie MeSH
- simulace molekulární dynamiky * MeSH
- telomery chemie MeSH
- vodíková vazba MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
- přehledy MeSH
- Research Support, N.I.H., Extramural MeSH
- Research Support, U.S. Gov't, Non-P.H.S. MeSH
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.
Acanthamoeba species are capable of causing amoebic keratitis (AK). As a monotherapy, alpha-mangostin is effective for the treatment of AK; however, its bioavailability is quite poor. Moreover, the efficacy of therapy is contingent on the parasite and virulent strains. To improve readiness against AK, it is necessary to find other derivatives with accurate target identification. Beta-tubulin (BT) has been used as a target for anti-Acanthamoeba (A. keratitis). In this work, therefore, a model of the BT protein of A. keratitis was constructed by homology modeling utilizing the amino acid sequence from NCBI (GenBank: JQ417907.1). Ramachandran Plot was responsible for validating the protein PDB. The verified BT PDB was used for docking with the specified ligand. Based on an improved docking score compared to alpha-mangostin (AM), two modified compounds were identified: 1,6-dihydroxy-7-methoxy-2,8-bis(3-methylbut-2-en-1-yl)-9H-xanthen-9-one (C1) and 1,6-dihydroxy-2,8-bis(3-methylbut-2-en-1-yl)-9H-xanthen-9-one (C2). In addition, molecular dynamics simulations were conducted to analyze the interaction characteristics of the two bound BT-new compound complexes. During simulations, the TRP9, ARG50, VAL52, and GLN122 residues of BT-C1 that align to the identical residues in BT-AM generate consistent hydrogen bond interactions with 0-3 and 0-2. However, the BT-C2 complex has a different binding site, TYR 258, ILE 281, and SER 302, and can form more hydrogen bonds in the range 0-4. Therefore, this study reveals that C1 and C2 inhibit BT as an additive or synergistic effect; however, further in vitro and in vivo studies are needed.
- MeSH
- Acanthamoeba * MeSH
- akantamébová keratitida * parazitologie MeSH
- lidé MeSH
- ligandy MeSH
- simulace molekulární dynamiky MeSH
- simulace molekulového dockingu MeSH
- tubulin MeSH
- xantony MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články 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
- elektrická stimulace * metody MeSH
- lidé MeSH
- simulace molekulární dynamiky * MeSH
- statická elektřina MeSH
- tubulin fyziologie MeSH
- vazebná místa MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
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.
Human stimulator of interferon genes (hSTING) is a signaling adaptor protein that triggers innate immune system by response to cytosolic DNA and second messenger cyclic dinucleotides (CDNs). Natural CDNs contain purine nucleobase with different phosphodiester linkage types (3'-3', 2'-2' or mixed 2'-3'-linkages) and exhibit different binding affinity towards hSTING, ranging from micromolar to nanomolar. High-affinity CDNs are considered as suitable candidates for treatment of chronic hepatitis B and cancer. We have used molecular dynamics simulations to investigate dynamical aspects of binding of natural CDNs (specifically, 2'-2'-cGAMP, 2'-3'-cGAMP, 3'-3'-cGAMP, 3'-3'-c-di-AMP, and 3'-3'-c-di-GMP) with hSTINGwt protein. Our results revealed that CDN/hSTINGwt interactions are controlled by the balance between fluctuations (conformational changes) in the CDN ligand and the protein dynamics. Binding of different CDNs induces different degrees of conformational/dynamics changes in hSTINGwt ligand binding cavity, especially in α1-helices, the so-called lid region and α2-tails. The ligand residence time in hSTINGwt protein pocket depends on different contribution of R232 and R238 residues interacting with oxygen atoms of phosphodiester groups in ligand, water distribution around interacting charged centers (in protein residues and ligand) and structural stability of closed conformation state of hSTINGwt protein. These findings may perhaps guide design of new compounds modulating hSTING activity.Communicated by Ramaswamy H. Sarma.
- MeSH
- dinukleosidfosfáty * chemie MeSH
- DNA MeSH
- lidé MeSH
- ligandy MeSH
- oligonukleotidy MeSH
- simulace molekulární dynamiky * MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
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.
