Physics-based predictions of RNA loop stability and structures

2012 ◽  
Author(s):  
◽  
Liang Liu
Keyword(s):  
Free Energy ◽  
Building Blocks ◽  
Conformational Ensemble ◽  
Scoring Functions ◽  
Rna Structures ◽  
Cellular Functions ◽  
Entropy Model ◽  
University Of Missouri ◽  
Knowledge Based ◽  
Three Body

[ACCESS RESTRICTED TO THE UNIVERSITY OF MISSOURI AT AUTHOR'S REQUEST.] RNA (ribonucleic acid) molecules play a variety of crucial roles in cellular functions at the level of transcription, translation and gene regulation. RNA functions are tied to structures. We aim to develop a novel free energy-based model for RNA structures, especially for RNA loops and junctions. In the first project, we develop a new conformational entropy model for RNA structures consisting of multiple helices connected by cross-linked loops. The basic strategy of our approach is to decompose the whole structure into a number of three-body building blocks, where each building block consists of a loop and two helices that are directly connected to the two ends of the loop. Assembly of the building blocks gives the entropy of the whole structure. The method provide a solid first step toward a systematic development of an entropy and free energy model for complex tertiary folds for RNA and other biopolymer. In the second project, based on the survey of all the known RNA structures, we derive a set of virtual bond-based scoring functions for the different types of dinucleotides. To circumvent the problem of reference state selection, we apply an iterative method to extract the effective potential, based on the complete conformational ensemble. With such a set of knowledge-based energy parameters, for a given sequence, we can successfully identify the native structure (the best-scored structure) from a set of structural decoys.

Physics-based predictions of RNA loop stability and structures

2012 ◽  
Author(s):  
◽  
Liang Liu
Keyword(s):  
Free Energy ◽  
Building Block ◽  
Structure Prediction ◽  
Building Blocks ◽  
Conformational Ensemble ◽  
Loop Structure ◽  
Scoring Functions ◽  
Rna Structures ◽  
Energy Parameters ◽  
Three Body

[ACCESS RESTRICTED TO THE UNIVERSITY OF MISSOURI AT AUTHOR'S REQUEST.] RNA (ribonucleic acid) molecules play a variety of crucial roles in cellular functions at the level of transcription, translation and gene regulation. RNA functions are tied to structures. In parallel to the experimental determination of RNA structures, such as X-ray crystallography and NMR spectroscopy, which can be laborious, time-consuming and expensive, it is imperative to develop a reliable theoretical/computational model for RNA structure prediction from its sequence. We aim to develop a novel free energy-based model for RNA structures, especially for RNA loops and junctions. One of the major roadblocks for the physics-based RNA tertiary structure prediction is the evaluation of the entropy for RNA tertiary folds. In particular, the entropies of structures with multiple loops and helices can be highly convoluted due to the volume exclusion between the loops and helices. In the first project, we develop a new conformational entropy model for RNA structures consisting of multiple helices connected by cross-linked loops. The basic strategy of our approach is to decompose the whole structure into a number of three-body building blocks, where each building block consists of a loop and two helices that are directly connected to the two ends of the loop. The simple construct of the three-body system allows for accurate computation of the conformational entropy for each building block. Assembly of the building blocks gives the entropy of the whole structure. This approach enables treatment of a large class of RNA tertiary folds. Tests against exact computer enumeration indicate that the method can yield accurate results for the entropy. The method provide a solid first step toward a systematic development of an entropy and free energy model for complex tertiary folds for RNA and other biopolymer. In the second project, we developed a novel approach to the prediction of loop structures from the sequence. The current loop free energy parameters (such as the Turner rules) depend only on the loop length and ignore the loop sequence-dependence. Such an oversimplification can lead to significant inaccuracies in the prediction of loop structure and stability. Here we tackle the problem by extracting the sequence-dependent scoring functions from the known loop structures. Specifically, based on the survey of all the known RNA structures, we derive a set of virtual bond-based scoring functions for the different types of dinucleotides. To circumvent the problem of reference state selection, we apply an iterative method to extract the effective potential, based on the complete conformational ensemble. This new new method has two notable advantages: (1) the statistical potential is extracted from the complete conformational ensemble, including the nonnative structures, (2) the method predicts low-energy loop structures from the sequence without additional information such as the homologous structural template. With such a set of knowledge-based energy parameters, for a given sequence, we can successfully identify the native structure (the best-scored structure) from a set of structural decoys. Our extensive benchmark tests show consistently encouraging success rates in the coarse-grained loop structure predictions.

scholarly journals An efficient use of X-ray information, homology modeling, molecular dynamics and knowledge-based docking techniques to predict protein–monosaccharide complexes

Glycobiology ◽  
2018 ◽  
Vol 29 (2) ◽  
pp. 124-136 ◽  
Author(s):  
Juan I Blanco Capurro ◽  
Matias Di Paola ◽  
Marcelo Daniel Gamarra ◽  
Marcelo A Martí ◽  
Carlos P Modenutti
Keyword(s):  
Molecular Dynamics ◽  
Model Building ◽  
Essential Element ◽  
Homology Model ◽  
Conformational Ensemble ◽  
Scoring Functions ◽  
Knowledge Based ◽  
Hydrophilic Nature ◽  
Conformational Diversity ◽  
Biological Recognition

Abstract Unraveling the structure of lectin–carbohydrate complexes is vital for understanding key biological recognition processes and development of glycomimetic drugs. Molecular Docking application to predict them is challenging due to their low affinity, hydrophilic nature and ligand conformational diversity. In the last decade several strategies, such as the inclusion of glycan conformation specific scoring functions or our developed solvent-site biased method, have improved carbohydrate docking performance but significant challenges remain, in particular, those related to receptor conformational diversity. In the present work we have analyzed conventional and solvent-site biased autodock4 performance concerning receptor conformational diversity as derived from different crystal structures (apo and holo), Molecular Dynamics snapshots and Homology-based models, for 14 different lectin–monosaccharide complexes. Our results show that both conventional and biased docking yield accurate lectin–monosaccharide complexes, starting from either apo or homology-based structures, even when only moderate (45%) sequence identity templates are available. An essential element for success is a proper combination of a middle-sized (10–100 structures) conformational ensemble, derived either from Molecular dynamics or multiple homology model building. Consistent with our previous works, results show that solvent-site biased methods improve overall performance, but that results are still highly system dependent. Finally, our results also show that docking can select the correct receptor structure within the ensemble, underscoring the relevance of joint evaluation of both ligand pose and receptor conformation.

scholarly journals A new entropy model for RNA: part III. Is the folding free energy landscape of RNA funnel shaped?

2014 ◽  
Vol 5 (1) ◽  
Author(s):  
Wayne Dawson ◽  
Toshikuni Takai ◽  
Nobuharu Ito ◽  
Kentaro Shimizu ◽  
Gota Kawai
Keyword(s):  
Free Energy ◽  
Degrees Of Freedom ◽  
Binding Free Energy ◽  
Relative Difference ◽  
Rna Structures ◽  
Native State ◽  
Rna Sequences ◽  
Entropy Model ◽  
Complex Protein ◽  
Folding Free Energy

The concept of a free energy (FE) landscape, in which the conformations of a polymer progressively take on the structure of the native state while spiraling down a FE surface that resembles the shape of a funnel, has long been viewed as the reason why a complex protein structure forms so rapidly compared to the number of conformations available to it. On the other hand, this landscape picture is less clear with RNA due to the multiplicity of conformations and the uncertainties in the current thermodynamics. It is therefore sometimes proposed that within the ensemble of suboptimal states of the RNA molecule, the vast majority of those states all closely resemble the native state and therefore simply overwhelm the few states that represent the global minimum FE. However, calculations of the free energy of observed structures often suggest that the most frequently observed cluster of structures are far from the minimum FE, particularly in the case of long sequences. If so, then such a FE surface is unlikely to be funnel shaped. We have been developing a version of <em>vsfold</em> that can evaluate the suboptimal structures of the FE surface (through a modified version called <em>vs_subopt</em>). Here we show that the ensemble of suboptimal structures for a number of known RNA structures can actually be both close to the minimum FE and also be the dominant observed structure when a proper Kuhn length is selected. Two state aptamers known as riboswitches can show neighboring FE states in the suboptimal structures that match the observed structures and their relative difference in FE is well within the range of the binding free energy of the metabolite. For the riboswitches and other short RNA sequences (less than 250 nt), the flow of the suboptimal structures (including pseudoknots) tended to resemble a rock rolling down a hill along the reaction coordinate axis. An important insight yielded by the cross-linking entropy (CLE) model is that the global entropy limits the size of domains. Hence, based on the CLE model, Levinthal’s paradox is overcome by the funnel shape in the FE, by a reduction in the number of degrees of freedom due to Kuhn length, and by limits on the size of the domains that can form. These concepts are also applicable to calculating transition rates between different suboptimal structures.

Are distance-dependent statistical potentials considering three interacting bodies superior to two-body statistical potentials for protein structure prediction?

2014 ◽  
Vol 12 (05) ◽  
pp. 1450022 ◽  
Author(s):  
Hamed Tabatabaei Ghomi ◽  
Jared J. Thompson ◽  
Markus A. Lill
Keyword(s):  
Free Energy ◽  
Protein Structure ◽  
Protein Structure Prediction ◽  
Structure Prediction ◽  
Protein Structures ◽  
Coarse Grained ◽  
Scoring Functions ◽  
Statistical Potentials ◽  
Three Body ◽  
Multi Body

Distance-based statistical potentials have long been used to model condensed matter systems, e.g. as scoring functions in differentiating native-like protein structures from decoys. These scoring functions are based on the assumption that the total free energy of the protein can be calculated as the sum of pairwise free energy contributions derived from a statistical analysis of pair-distribution functions. However, this fundamental assumption has been challenged theoretically. In fact the free energy of a system with N particles is only exactly related to the N-body distribution function. Based on this argument coarse-grained multi-body statistical potentials have been developed to capture higher-order interactions. Having a coarse representation of the protein and using geometric contacts instead of pairwise interaction distances renders these models insufficient in modeling details of multi-body effects. In this study, we investigated if extending distance-dependent pairwise atomistic statistical potentials to corresponding interaction functions that are conditional on a third interacting body, defined as quasi-three-body statistical potentials, could model details of three-body interactions. We also tested if this approach could improve the predictive capabilities of statistical scoring functions for protein structure prediction. We analyzed the statistical dependency between two simultaneous pairwise interactions and showed that there is surprisingly little if any dependency of a third interacting site on pairwise atomistic statistical potentials. Also the protein structure prediction performance of these quasi-three-body potentials is comparable with their corresponding two-body counterparts. The scoring functions developed in this study showed better or comparable performances compared to some widely used scoring functions for protein structure prediction.

The diverse roles of the Nup93/Nic96 complex proteins – structural scaffolds of the nuclear pore complex with additional cellular functions

2014 ◽  
Vol 395 (5) ◽  
pp. 515-528 ◽  
Author(s):  
Benjamin Vollmer ◽  
Wolfram Antonin
Keyword(s):  
Nuclear Pore Complex ◽  
Nuclear Membrane ◽  
Building Blocks ◽  
Transport Processes ◽  
Nuclear Pore ◽  
Nuclear Pore Complexes ◽  
Cellular Functions ◽  
Complex Assembly ◽  
Essential Function ◽  
Pore Complexes

Abstract Nuclear pore complexes mediate the transport between the cell nucleoplasm and cytoplasm. These 125 MDa structures are among the largest assemblies found in eukaryotes, built from proteins organized in distinct subcomplexes that act as building blocks during nuclear pore complex biogenesis. In this review, we focus on one of these subcomplexes, the Nup93 complex in metazoa and its yeast counterpart, the Nic96 complex. We discuss its essential function in nuclear pore complex assembly as a linker between the nuclear membrane and the central part of the pore and its various roles in nuclear transport processes and beyond.

scholarly journals Microhydration of ionized building blocks of DNA/RNA: infrared spectra of pyrimidine$$^{+}$$-$$(\hbox {H}_{2}\hbox {O})_{\text {1-3}}$$ clusters

2021 ◽  
Vol 75 (3) ◽  
Author(s):  
Kuntal Chatterjee ◽  
Otto Dopfer
Keyword(s):  
Density Functional ◽  
Size Range ◽  
Density Functional Theory Calculations ◽  
Building Blocks ◽  
Ion Solvation ◽  
Structure Stability ◽  
Consistent Picture ◽  
Three Body ◽  
And Function ◽  
Stable Structures

Abstract Hydration of biomolecules is an important physiological process that governs their structure, stability, and function. Herein, we probe the microhydration structure of cationic pyrimidine (Pym), a common building block of DNA/RNA bases, by infrared photodissociation spectroscopy (IRPD) of mass-selected microhydrated clusters, $$\hbox {Pym}^{+}$$ Pym + -$$\hbox {W}_{n}$$ W n (W=$$\hbox {H}_{2}\hbox {O}$$ H 2 O ), in the size range $$n=1$$ n = 1 –3. The IRPD spectra recorded in the OH and CH stretch range are sensitive to the evolution of the hydration network. Analysis with density functional theory calculations at the dispersion-corrected B3LYP-D3/aug-cc-pVTZ level provides a consistent picture of the most stable structures and their energetic and vibrational properties. The global minima of $$\hbox {Pym}^{+}$$ Pym + -$$\hbox {W}_{n}$$ W n predicted by the calculations are characterized by H-bonded structures, in which the H-bonded $$\hbox {W}_{n}$$ W n solvent cluster is attached to the most acidic C4–H proton of $$\hbox {Pym}^{+}$$ Pym + via a single CH...O ionic H-bond. These isomers are identified as predominant carrier of the IRPD spectra, although less stable local minima provide minor contributions. In general, the formation of the H-bonded solvent network (exterior ion solvation) is energetically preferred to less stable structures with interior ion solvation because of cooperative nonadditive three-body polarization effects. Progressive hydration activates the C4–H bond, along with increasing charge transfer from $$\hbox {Pym}^{+}$$ Pym + to $$\hbox {W}_{n}$$ W n , although no proton transfer is observed in the size range $$n\leqslant $$ n ⩽ 3. The solvation with protic, dipolar, and hydrophilic W ligands is qualitative different from solvation with aprotic, quadrupolar, and hydrophobic $$\hbox {N}_{2}$$ N 2 ligands, which strongly prefer interior ion solvation by $$\uppi $$ π stacking interactions. Comparison of $$\hbox {Pym}^{+}$$ Pym + -W with Pym-W and $$\hbox {H}^{+}$$ H + Pym-W reveals the drastic effect of ionization and protonation on the Pym...W interaction. Graphic Abstract

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