Nucleic acid double helices in their DNA, RNA, and DNA-RNA hybrid form play a fundamental role in biology and are main building blocks of artificial nanostructures, but how their properties depend on temperature remains poorly understood. Here, we report thermal dependence of dynamic bending persistence length, twist rigidity, stretch modulus, and twist-stretch coupling for DNA, RNA, and hybrid duplexes between 7°C and 47°C. The results are based on all-atom molecular dynamics simulations using different force field parameterizations. We first demonstrate that unrestrained molecular dynamics can reproduce experimentally known mechanical properties of the duplexes at room temperature. Beyond experimentally known features, we also infer the twist rigidity and twist-stretch coupling of the hybrid duplex. As for the temperature dependence, we found that increasing temperature softens all the duplexes with respect to bending, twisting, and stretching. The relative decrease of the stretch moduli is 0.003-0.004/°C, similar for all the duplex variants despite their very different stretching stiffness, whereas RNA twist stiffness decreases by 0.003/°C, and smaller values are found for the other elastic moduli. The twist-stretch couplings are nearly unaffected by temperature. The stretching, bending, and twisting stiffness all include an important entropic component. Relation of our results to the two-state model of DNA flexibility is discussed. Our work provides temperature-dependent elasticity of nucleic acid duplexes at the microsecond scale relevant for initial stages of protein binding.

• MeSH
• DNA * chemie   MeSH
• konformace nukleové kyseliny MeSH
• pružnost MeSH
• RNA * chemie   MeSH
• teplota MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• DNA * MeSH
• RNA * 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.

• MeSH
• DNA chemie   MeSH
• katalýza MeSH
• konformace nukleové kyseliny * MeSH
• počítačová simulace MeSH
• RNA chemie   MeSH
• simulace molekulární dynamiky * MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• přehledy MeSH
• Research Support, N.I.H., Extramural MeSH
• Názvy látek
• DNA MeSH
• RNA MeSH

We present a systematic study of the long-timescale dynamics of the Drew-Dickerson dodecamer (DDD: d(CGCGAATTGCGC)2) a prototypical B-DNA duplex. Using our newly parameterized PARMBSC1 force field, we describe the conformational landscape of DDD in a variety of ionic environments from minimal salt to 2 M Na(+)Cl(-) or K(+)Cl(-) The sensitivity of the simulations to the use of different solvent and ion models is analyzed in detail using multi-microsecond simulations. Finally, an extended (10 μs) simulation is used to characterize slow and infrequent conformational changes in DDD, leading to the identification of previously uncharacterized conformational states of this duplex which can explain biologically relevant conformational transitions. With a total of more than 43 μs of unrestrained molecular dynamics simulation, this study is the most extensive investigation of the dynamics of the most prototypical DNA duplex.

• MeSH
• B-DNA chemie   ultrastruktura   MeSH
• chlorid draselný chemie   MeSH
• chlorid sodný chemie   MeSH
• konformace nukleové kyseliny * MeSH
• molekulární modely MeSH
• simulace molekulární dynamiky * MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• B-DNA MeSH
• chlorid draselný MeSH
• chlorid sodný MeSH

The Dickerson-Drew dodecamer (DD) d-[CGCGAATTCGCG]2 is a prototypic B-DNA molecule whose sequence-specific structure and dynamics have been investigated by many experimental and computational studies. Here, we present an analysis of DD properties based on extensive atomistic molecular dynamics (MD) simulations using different ionic conditions and water models. The 0.6-2.4-µs-long MD trajectories are compared to modern crystallographic and NMR data. In the simulations, the duplex ends can adopt an alternative base-pairing, which influences the oligomer structure. A clear relationship between the BI/BII backbone substates and the basepair step conformation has been identified, extending previous findings and exposing an interesting structural polymorphism in the helix. For a given end pairing, distributions of the basepair step coordinates can be decomposed into Gaussian-like components associated with the BI/BII backbone states. The nonlocal stiffness matrices for a rigid-base mechanical model of DD are reported for the first time, suggesting salient stiffness features of the central A-tract. The Riemann distance and Kullback-Leibler divergence are used for stiffness matrix comparison. The basic structural parameters converge very well within 300 ns, convergence of the BI/BII populations and stiffness matrices is less sharp. Our work presents new findings about the DD structural dynamics, mechanical properties, and the coupling between basepair and backbone configurations, including their statistical reliability. The results may also be useful for optimizing future force fields for DNA.

• Publikační typ
• časopisecké články MeSH

Hybrid QM/MM methods combine the rigor of quantum mechanical (QM) calculations with the low computational cost of empirical molecular mechanical (MM) treatment allowing to capture dynamic properties to probe critical atomistic details of enzyme reactions. Catalysis by RNA enzymes (ribozymes) has only recently begun to be addressed with QM/MM approaches and is thus still a field under development. This review surveys methodology as well as recent advances in QM/MM applications to RNA mechanisms, including those of the HDV, hairpin, and hammerhead ribozymes, as well as the ribosome. We compare and correlate QM/MM results with those from QM and/or molecular dynamics (MD) simulations, and discuss scope and limitations with a critical eye on current shortcomings in available methodologies and computer resources. We thus hope to foster mutual appreciation and facilitate collaboration between experimentalists and theorists to jointly advance our understanding of RNA catalysis at an atomistic level.

• MeSH
• biofyzika metody   MeSH
• fosfáty chemie   MeSH
• fosforylace MeSH
• hořčík chemie   MeSH
• katalýza MeSH
• konformace nukleové kyseliny MeSH
• kvantová teorie MeSH
• lidé MeSH
• molekulární modely MeSH
• počítačová simulace MeSH
• ribozomy chemie   MeSH
• RNA katalytická chemie   MeSH
• RNA virová chemie   MeSH
• RNA chemie   MeSH
• software MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• přehledy MeSH
• Research Support, N.I.H., Extramural MeSH
• Názvy látek
• fosfáty MeSH
• hammerhead ribozyme MeSH Prohlížeč
• hořčík MeSH
• RNA katalytická MeSH
• RNA virová MeSH
• RNA MeSH

Explicit solvent molecular dynamics simulations (in total almost 800 ns including locally enhanced sampling runs) were applied with different ion conditions and with two force fields (AMBER and CHARMM) to characterize typical geometries adopted by the flanking bases in the RNA kissing-loop complexes. We focus on flanking base positions in multiple x-ray and NMR structures of HIV-1 DIS kissing complexes and kissing complex from the large ribosomal subunit of Haloarcula marismortui. An initial x-ray open conformation of bulged-out bases in HIV-1 DIS complexes, affected by crystal packing, tends to convert to a closed conformation formed by consecutive stretch of four stacked purine bases. This is in agreement with those recent crystals where the packing is essentially avoided. We also observed variants of the closed conformation with three stacked bases, while nonnegligible populations of stacked geometries with bulged-in bases were detected, too. The simulation results reconcile differences in positions of the flanking bases observed in x-ray and NMR studies. Our results suggest that bulged-out geometries are somewhat more preferred, which is in accord with recent experiments showing that they may mediate tertiary contacts in biomolecular assemblies or allow binding of aminoglycoside antibiotics.

• MeSH
• chemické modely * MeSH
• dimerizace MeSH
• HIV-1 chemie   genetika   MeSH
• konformace nukleové kyseliny MeSH
• molekulární modely * MeSH
• párování bází genetika   MeSH
• počátek transkripce * MeSH
• počítačová simulace MeSH
• RNA virová chemie   MeSH
• vazebná místa MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• RNA virová MeSH

This review provides a critical assessment of the advantages and limitations of modeling methods available for guanine quadruplex (G-DNA) molecules. We characterize the relations of simulations to the experimental techniques and explain the actual meaning and significance of the results. The following aspects are discussed: pair-additive approximation of the empirical force fields, sampling limitations stemming from the simulation time and accuracy of description of base stacking, H-bonding, sugar-phosphate backbone and ions by force fields. Several methodological approaches complementing the classical explicit solvent molecular dynamics simulations are commented on, including enhanced sampling methods, continuum solvent methods, free energy calculations and gas phase simulations. The successes and pitfalls of recent simulation studies of G-DNA are demonstrated on selected results, including studies of cation interactions and dynamics of G-DNA stems, studies of base substitutions (inosine, thioguanine and mixed tetrads), analysis of possible kinetic intermediates in folding pathway of a G-DNA stem and analysis of loop regions of G-DNA molecules.

• MeSH
• DNA chemie   MeSH
• G-kvadruplexy * MeSH
• guanin chemie   MeSH
• ligandy MeSH
• molekulární modely MeSH
• počítačová simulace MeSH
• termodynamika MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• DNA MeSH
• guanin MeSH
• ligandy MeSH

The hepatitis delta virus (HDV) ribozyme is an RNA enzyme from the human pathogenic HDV. Cations play a crucial role in self-cleavage of the HDV ribozyme, by promoting both folding and chemistry. Experimental studies have revealed limited but intriguing details on the location and structural and catalytic functions of metal ions. Here, we analyze a total of approximately 200 ns of explicit-solvent molecular dynamics simulations to provide a complementary atomistic view of the binding of monovalent and divalent cations as well as water molecules to reaction precursor and product forms of the HDV ribozyme. Our simulations find that an Mg2+ cation binds stably, by both inner- and outer-sphere contacts, to the electronegative catalytic pocket of the reaction precursor, in a position to potentially support chemistry. In contrast, protonation of the catalytically involved C75 in the precursor or artificial placement of this Mg2+ into the product structure result in its swift expulsion from the active site. These findings are consistent with a concerted reaction mechanism in which C75 and hydrated Mg2+ act as general base and acid, respectively. Monovalent cations bind to the active site and elsewhere assisted by structurally bridging long-residency water molecules, but are generally delocalized.

• MeSH
• hořčík chemie   MeSH
• kationty dvojmocné chemie   MeSH
• kationty jednomocné chemie   MeSH
• konformace nukleové kyseliny MeSH
• molekulární modely MeSH
• molekulární sekvence - údaje MeSH
• RNA katalytická chemie   MeSH
• sekvence nukleotidů MeSH
• sodík chemie   MeSH
• vazebná místa MeSH
• virus hepatitidy delta enzymologie   MeSH
• voda chemie   MeSH
• vodíková vazba MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Research Support, N.I.H., Extramural MeSH
• Názvy látek
• hořčík MeSH
• kationty dvojmocné MeSH
• kationty jednomocné MeSH
• RNA katalytická MeSH
• sodík MeSH
• voda MeSH

Explicit solvent molecular dynamics (MD) simulations were carried out for sarcin-ricin domain (SRD) motifs from 23S (Escherichia coli) and 28S (rat) rRNAs. The SRD motif consists of GAGA tetraloop, G-bulged cross-strand A-stack, flexible region and duplex part. Detailed analysis of the overall dynamics, base pairing, hydration, cation binding and other SRD features is presented. The SRD is surprisingly static in multiple 25 ns long simulations and lacks any non-local motions, with root mean square deviation (r.m.s.d.) values between averaged MD and high-resolution X-ray structures of 1-1.4 A. Modest dynamics is observed in the tetraloop, namely, rotation of adenine in its apex and subtle reversible shift of the tetraloop with respect to the adjacent base pair. The deformed flexible region in low-resolution rat X-ray structure is repaired by simulations. The simulations reveal few backbone flips, which do not affect positions of bases and do not indicate a force field imbalance. Non-Watson-Crick base pairs are rigid and mediated by long-residency water molecules while there are several modest cation-binding sites around SRD. In summary, SRD is an unusually stiff rRNA building block. Its intrinsic structural and dynamical signatures seen in simulations are strikingly distinct from other rRNA motifs such as Loop E and Kink-turns.

• MeSH
• endoribonukleasy metabolismus   MeSH
• Escherichia coli genetika   MeSH
• fungální proteiny metabolismus   MeSH
• kationty chemie   MeSH
• konformace nukleové kyseliny MeSH
• krysa rodu Rattus MeSH
• krystalografie rentgenová MeSH
• molekulární modely * MeSH
• párování bází MeSH
• počítačová simulace MeSH
• ricin metabolismus   MeSH
• RNA ribozomální 23S chemie   metabolismus   MeSH
• RNA ribozomální 28S chemie   metabolismus   MeSH
• sacharidy chemie   MeSH
• vazebná místa MeSH
• voda chemie   MeSH
• vodíková vazba MeSH
• zvířata MeSH
• Check Tag
• krysa rodu Rattus MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Research Support, U.S. Gov't, Non-P.H.S. MeSH
• Názvy látek
• alpha-sarcin MeSH Prohlížeč
• endoribonukleasy MeSH
• fungální proteiny MeSH
• kationty MeSH
• ricin MeSH
• RNA ribozomální 23S MeSH
• RNA ribozomální 28S MeSH
• sacharidy MeSH
• voda MeSH