Exploring the Energy Landscape of a Small RNA Hairpin

Ma, Hao; Proctor, David J.; Kierzek, Elżbieta; Kierzek, Ryszard; Bevilacqua, Philip C.; Gruebele, Martin

doi:10.1021/ja0553856

Cited by 137 publications

(253 citation statements)

References 32 publications

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“…The ruggedness of the folding free-energy landscapes of nucleic acid hairpins has been explored in several experiments using temperature jump methods to monitor kinetic transitions away from the melting temperature (10,20,45). Based on rates of refolding, these studies identified ensembles of partially stacked structures in submelting regions.…”

Section: Discussionmentioning

confidence: 99%

“…These tetraloop structures have been explored through multiple experimental (16)(17)(18)(19)(20)(21)(22)(23) and computational (24)(25)(26)(27) analyses that have revealed important clues about RNA thermodynamic stability and relate to the processes that govern the formation and stabilization of basic RNA molecules. Many tetraloops containing the conserved nucleotide sequence GNRA (N = A,C, G,U; R = A,G) possess an inherent global flexibility that manifests through multiple configurational states (19,21,22,28).…”

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confidence: 99%

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Free-energy landscape of a hyperstable RNA tetraloop

Miner

Chen

Garcı́a

2016

Proc. Natl. Acad. Sci. U.S.A.

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We report the characterization of the energy landscape and the folding/unfolding thermodynamics of a hyperstable RNA tetraloop obtained through high-performance molecular dynamics simulations at microsecond timescales. Sampling of the configurational landscape is conducted using temperature replica exchange molecular dynamics over three isochores at high, ambient, and negative pressures to determine the thermodynamic stability and the freeenergy landscape of the tetraloop. The simulations reveal reversible folding/unfolding transitions of the tetraloop into the canonical A-RNA conformation and the presence of two alternative configurations, including a left-handed Z-RNA conformation and a compact purine Triplet. Increasing hydrostatic pressure shows a stabilizing effect on the A-RNA conformation and a destabilization of the lefthanded Z-RNA. Our results provide a comprehensive description of the folded free-energy landscape of a hyperstable RNA tetraloop and highlight the significant advances of all-atom molecular dynamics in describing the unbiased folding of a simple RNA secondary structure motif.RNA | free-energy landscape | molecular dynamics | tetraloop | pressure T he stability of a folded RNA molecule depends on a complex set of interactions between the RNA with itself and the surrounding environment. Secondary RNA structures fold by a combination of complimentary base pairing, nucleotide stacking, and screening of the anionic phosphate backbone (1), but these interactions depend heavily on the local solution environment, and the RNA configuration can be either stabilized or destabilized by a number of extrinsic factors, including temperature (2), pressure (3), denaturants, and salt concentration (4). Even in simple RNA duplexes, changes in pressure and ion concentrations have been shown to drive the formation of alternative configurations (5, 6) and change the RNA folded ensemble. Characterizing the effects that these different factors have on the folded free-energy landscape of RNA is crucial for determining the thermodynamic stability of different RNA motifs and the probability of transitions between configurations.Small RNA hairpins have been used as a model system for characterizing RNA folding and stability for decades because of their small size, their ubiquitous presence in many natural systems, and the complexity of their internal interactions (7-11). Hairpins result when a single oligonucleotide strand bends 180°t o form an antiparallel duplex through complementary base pairing. The bent, single-stranded loop region is capable of forming complex hydrogen bond networks (12) or long-range interactions with other RNAs (13). Some of the most thermodynamically stable RNA hairpins form loop regions of 4 nt, called tetraloops (14), which are highly compact, structurally conserved, and typically stabilized by the formation of a network of hydrogen bonds (15) that decrease the loop conformational entropy.These tetraloop structures have been explored through multiple experimental (16-23) and computational...

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Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

Free-energy landscape of a hyperstable RNA tetraloop

Miner

Chen

Garcı́a

2016

Proc. Natl. Acad. Sci. U.S.A.

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“…23,33,34 The number of experimentally determined high resolution RNA structures 30,31,35 continues to increase, enabling us to understand the interactions that stabilize the folded states. Single molecule [36][37][38][39][40][41] and ensemble experiments [42][43][44] using a variety of biophysical methods combined with theoretical techniques 14,34 have led to a conceptual framework for predicting various mechanisms by which RNA molecules fold. In order to make further progress new computational tools are required.…”

Section: Introductionmentioning

confidence: 99%

Minimal Models for Proteins and RNA: From Folding to Function

Pincus

Cho

Hyeon

et al. 2008

Progress in Molecular Biology and Translational Science

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We present a panoramic view of the utility of coarse-grained (CG) models to study folding and functions of proteins and RNA. Drawing largely on the methods developed in our group over the last twenty years, we describe a number of key applications ranging from folding of proteins with disulfide bonds to functions of molecular machines. After presenting the theoretical basis that justifies the use of CG models, we explore the biophysical basis for the emergence of a finite number of folds from lattice models. The lattice model simulations of approach to the folded state show that non-native interactions are relevant only early in the folding process -a finding that rationalizes the success of structure-based models that emphasize native interactions. Applications of off-lattice C α and models that explicitly consider side chains (C α -SCM) to folding of β-hairpin and effects of macromolecular crowding are briefly discussed. Successful applications of a new class of off-lattice models, referred to as the Self- We also present two distinct models for RNA, namely, the Three Site Interaction (TIS) model and the SOP model, that probe forced unfolding and force quench refolding of a simple hairpin and Azoarcus ribozyme. The unfolding pathways of Azoarcus ribozyme depend on the loading rate, while constant force and constant loading rate simulations of the hairpin show that both forced-unfolding and force-quench refolding pathways are heterogeneous. The location of the transition state moves as force is varied. The predictions based on the SOP model show that force-induced unfolding pathways of the ribozyme can be dramatically changed by varying the loading rate. We conclude with a discussion of future prospects for the use of coarse-grained models in addressing problems of outstanding interest in biology.

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“…Hairpins are a fundamental RNA secondary structure motif (33) and perform many biologically relevant functions, but our understanding of their folding is still incomplete (34)(35)(36)(37)(38). The folding of this hairpin is diffusion controlled (37,39,40), so despite its small size, the folding time is on the microsecond time scale, as measured by laser temperature jump experiments (35). Thus, capturing a single folding event with a single MD simulation with explicit solvent would likely take more than a year on a typical CPU.…”

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confidence: 99%

Rapid equilibrium sampling initiated from nonequilibrium data

Huang

Bowman

Bacallado

et al. 2009

Proc. Natl. Acad. Sci. U.S.A.

157

179

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Simulating the conformational dynamics of biomolecules is extremely difficult due to the rugged nature of their free energy landscapes and multiple long-lived, or metastable, states. Generalized ensemble (GE) algorithms, which have become popular in recent years, attempt to facilitate crossing between states at low temperatures by inducing a random walk in temperature space. Enthalpic barriers may be crossed more easily at high temperatures; however, entropic barriers will become more significant. This poses a problem because the dominant barriers to conformational change are entropic for many biological systems, such as the short RNA hairpin studied here. We present a new efficient algorithm for conformational sampling, called the adaptive seeding method (ASM), which uses nonequilibrium GE simulations to identify the metastable states, and seeds short simulations at constant temperature from each of them to quantitatively determine their equilibrium populations. Thus, the ASM takes advantage of the broad sampling possible with GE algorithms but generally crosses entropic barriers more efficiently during the seeding simulations at low temperature. We show that only local equilibrium is necessary for ASM, so very short seeding simulations may be used. Moreover, the ASM may be used to recover equilibrium properties from existing datasets that failed to converge, and is well suited to running on modern computer clusters.generalized ensemble methods ͉ Markov state models ͉ molecular dynamics simulations ͉ RNA hairpin folding T he functions of biological macromolecules are in large part determined by their structure and dynamics. As such, many experimental techniques have been developed and applied to probe these properties, each of which has its strengths and weaknesses. Computational methods such as molecular dynamics (MD) and Monte Carlo (MC) simulations have the potential to complement such experiments by modeling the evolution of entire systems with atomic resolution. However, it is extremely difficult to obtain equilibrium sampling of even moderately sized systems in atomic simulations because of the rugged nature of the free energy landscapes that must be explored. Without adequate sampling, it is impossible to validate the parameters, or force fields, that determine the interactions between atoms or to address phenomena that occur on biologically relevant timescales.Many methods have been developed in an attempt to address the sampling problem. Generalized ensemble (GE) algorithms, such as the replica exchange method (REM), or parallel tempering (1, 2) and simulated tempering (ST) (3, 4), are popular approaches for studying biomolecular folding (5-15). They attempt to overcome the sampling problem by inducing a random walk in temperature space while maintaining canonical sampling at each temperature. At high temperatures, energetic barriers may be crossed easily; at low temperatures, the system is generally constrained to local minima. However, recent studies have shown that GE simulations do not yield conver...

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Exploring the Energy Landscape of a Small RNA Hairpin

Cited by 137 publications

References 32 publications

Free-energy landscape of a hyperstable RNA tetraloop

Free-energy landscape of a hyperstable RNA tetraloop

Minimal Models for Proteins and RNA: From Folding to Function

Rapid equilibrium sampling initiated from nonequilibrium data

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