scholarly journals Structural Landscape of the Transition from an ssDNA Dumbbell Plus Its Complementary Hairpin to a dsDNA Microcircle Via a Kissing Loop Intermediate

Molecules ◽  
2021 ◽  
Vol 26 (10) ◽  
pp. 3017
Author(s):  
Alberto Mills ◽  
Federico Gago
Keyword(s):  
Model Building ◽  
Three Dimensional ◽  
3D Models ◽  
Base Pairs ◽  
T4 Dna Ligase ◽  
Double Stranded Dna ◽  
Explicit Solvent ◽  
Dynamics Simulations ◽  
Enzyme Recognition ◽  
Kissing Loop

The experimental construction of a double-stranded DNA microcircle of only 42 base pairs entailed a great deal of ingenuity and hard work. However, figuring out the three-dimensional structures of intermediates and the final product can be particularly baffling. Using a combination of model building and unrestrained molecular dynamics simulations in explicit solvent we have characterized the different DNA structures involved along the process. Our 3D models of the single-stranded DNA molecules provide atomic insight into the recognition event that must take place for the DNA bases in the cohesive tail of the hairpin to pair with their complementary bases in the single-stranded loops of the dumbbell. We propose that a kissing loop involving six base pairs makes up the core of the nascent dsDNA microcircle. We also suggest a feasible pathway for the hybridization of the remaining complementary bases and characterize the final covalently closed dsDNA microcircle as possessing two well-defined U-turns. Additional models of the pre-ligation complex of T4 DNA ligase with the DNA dumbbell and the post-ligation pre-release complex involving the same enzyme and the covalently closed DNA microcircle are shown to be compatible with enzyme recognition and gap ligation.

scholarly journals Synchronized Oscillations in Double-Helix B-DNA Molecules with Mirror-Symmetric Codons

Symmetry ◽  
2021 ◽  
Vol 13 (2) ◽  
pp. 241
Author(s):  
Enrique Maciá
Keyword(s):  
Base Pair ◽  
Double Helix ◽  
Three Dimensional ◽  
Dna Molecules ◽  
Analytical Treatment ◽  
Dynamical Equations ◽  
Base Pairs ◽  
Double Stranded Dna ◽  
Collective Oscillations ◽  
Triplet Codon

A fully analytical treatment of the base-pair and codon dynamics in double-stranded DNA molecules is introduced, by means of a realistic treatment that considers different mass values for G, A, T, and C nucleotides and takes into account the intrinsic three-dimensional, helicoidal geometry of DNA in terms of a Hamitonian in cylindrical coordinates. Within the framework of the Peyrard–Dauxois–Bishop model, we consider the coupling between stretching and stacking radial oscillations as well as the twisting motion of each base pair around the helix axis. By comparing the linearized dynamical equations for the angular and radial variables corresponding to the bp local scale with those of the longer triplet codon scale, we report an underlying hierarchical symmetry. The existence of synchronized collective oscillations of the base-pairs and their related codon triplet units are disclosed from the study of their coupled dynamical equations. The possible biological role of these correlated, long-range oscillation effects in double standed DNA molecules containing mirror-symmetric codons of the form XXX, XX’X, X’XX’, YXY, and XYX is discussed in terms of the dynamical equations solutions and their related dispersion relations.

scholarly journals How a Hemicarcerand Incarcerates Guests at Room Temperature Decoded with Modular Simulations

2020 ◽  
Author(s):  
Katherine G. McFerrin ◽  
Yuan-Ping Pang
Keyword(s):  
Molecular Dynamics ◽  
Molecular Dynamics Simulations ◽  
Model Building ◽  
Three Dimensional ◽  
Building Blocks ◽  
Water Soluble ◽  
Modular Approach ◽  
Molecular Complexation ◽  
Three Dimensional Models ◽  
Dynamics Simulations

AbstractHemicarcerands are host molecules created to study constrictive binding with guest molecules for insights into the rules of molecular complexation. However, the molecular dynamics simulations that facilitate such studies have been limited because three-dimensional models of hemicarcerands are tedious to build and their atomic charges are complicated to derive. There have been no molecular dynamics simulations of the reported water-soluble hemicarcerand (Octacid4) that explain how it uniquely encapsulates its guests at 298 K and keeps them encapsulated at 298 K in NMR experiments. Herein we report a modular approach to hemicarcerand simulations that simplifies the model building and charge derivation in a manner reminiscent of the approach to protein simulations with truncated amino acids as building blocks. We also report that apo Octacid4 in water adopts two clusters of conformations, one of which has an equatorial portal open thus allowing guests to enter the cavity of Octacid4, in microsecond molecular dynamics simulations performed using the modular approach at 298 K. Under the same simulation conditions, the guest-bound Octacid4 adopts one cluster of conformations with all equatorial portals closed thus keeping the guests incarcerated. These results explain the unique constrictive binding of Octacid4 and suggest that the guest-induced host conformational change that impedes decomplexation is a previously unrecognized conformational characteristic that promotes strong molecular complexation.

scholarly journals Integrative Approach for Computationally Inferring Interactions between the Alpha and Beta Subunits of the Calcium-Activated Potassium Channel (BK): A Docking Study

2013 ◽  
Vol 7 ◽  
pp. BBI.S10077 ◽  
Author(s):  
Janneth González ◽  
Angela Gálvez ◽  
Ludis Morales ◽  
George E. Barreto ◽  
Francisco Capani ◽  
...  
Keyword(s):  
Potassium Channel ◽  
Model Building ◽  
Three Dimensional ◽  
Docking Study ◽  
3D Models ◽  
Accessible Surface Area ◽  
Potential Interaction ◽  
Integrative Approach ◽  
Interaction Sites ◽  
Calcium Activated Potassium Channel

Three-dimensional models of the alpha- and beta-1 subunits of the calcium-activated potassium channel (BK) were predicted by threading modeling. A recursive approach comprising of sequence alignment and model building based on three templates was used to build these models, with the refinement of non-conserved regions carried out using threading techniques. The complex formed by the subunits was studied by means of docking techniques, using 3D models of the two subunits, and an approach based on rigid-body structures. Structural effects of the complex were analyzed with respect to hydrogen-bond interactions and binding-energy calculations. Potential interaction sites of the complex were determined by referencing a study of the difference accessible surface area (DASA) of the protein subunits in the complex.

Binding patterns and dynamics of double-stranded DNA on the phosphorene surface

Nanoscale ◽  
2020 ◽  
Vol 12 (17) ◽  
pp. 9430-9439 ◽  
Author(s):  
Baoyu Li ◽  
Xuejie Xie ◽  
Guangxin Duan ◽  
Serena H. Chen ◽  
Xuan-Yu Meng ◽  
...  
Keyword(s):  
Molecular Dynamics ◽  
Molecular Dynamics Simulations ◽  
Base Pairs ◽  
Upright Orientation ◽  
Double Stranded Dna ◽  
Dynamics Simulations

Molecular dynamics simulations and electrophoresis experiments show that dsDNA can form a stable binding on the phosphorene surface through the terminal base pairs and adopt an upright orientation regardless of its initial configurations.

scholarly journals Dynamic Structure and Stability of DNA Duplexes Bearing a Dinuclear Hg(II)-Mediated Base Pair

Molecules ◽  
2020 ◽  
Vol 25 (21) ◽  
pp. 4942
Author(s):  
Jim Bachmann ◽  
Isabell Schönrath ◽  
Jens Müller ◽  
Nikos L. Doltsinis
Keyword(s):  
Base Pair ◽  
Metal Ion ◽  
Model Building ◽  
Dynamic Structure ◽  
Quantum Mechanical ◽  
Distance Constraint ◽  
Dna Duplexes ◽  
Base Pairs ◽  
Intramolecular Bonding ◽  
Dynamics Simulations

Quantum mechanical (QM) and hybrid quantum mechanical/molecular mechanical (QM/MM) molecular dynamics simulations of a recently reported dinuclear mercury(II)-mediated base pair were performed aiming to analyse its intramolecular bonding pattern, its stability, and to obtain clues on the mechanism of the incorporation of mercury(II) into the DNA. The dynamic distance constraint was employed to find initial structures, control the dissociation process in an unbiased fashion and to determine the free energy required. A strong influence of the exocyclic carbonyl or amino groups of neighbouring base pairs on both the bonding pattern and the mechanism of incorporation was observed. During the dissociation simulation, an amino group of an adenine moiety of the adjacent base pair acts as a turnstile to rotate the mercury(II) ion out of the DNA core region. The calculations provide an important insight into the mechanism of formation of this dinuclear metal-mediated base pair and indicate that the exact location of a transition metal ion in a metal-mediated base pair may be more ambiguous than derived from simple model building.

scholarly journals Ethidium bromide interactions with DNA: an exploration of a classic DNA–ligand complex with unbiased molecular dynamics simulations

2021 ◽  
Vol 49 (7) ◽  
pp. 3735-3747
Author(s):  
Rodrigo Galindo-Murillo ◽  
Thomas E Cheatham
Keyword(s):  
Molecular Dynamics ◽  
Molecular Dynamics Simulations ◽  
Ethidium Bromide ◽  
Base Pair ◽  
Force Fields ◽  
Ligand Complex ◽  
Base Pairs ◽  
Duplex System ◽  
Double Stranded Dna ◽  
Dynamics Simulations

Abstract Visualization of double stranded DNA in gels with the binding of the fluorescent dye ethidium bromide has been a basic experimental technique in any molecular biology laboratory for >40 years. The interaction between ethidium and double stranded DNA has been observed to be an intercalation between base pairs with strong experimental evidence. This presents a unique opportunity for computational chemistry and biomolecular simulation techniques to benchmark and assess their models in order to see if the theory can reproduce experiments and ultimately provide new insights. We present molecular dynamics simulations of the interaction of ethidium with two different double stranded DNA models. The first model system is the classic sequence d(CGCGAATTCGCG)2 also known as the Drew–Dickerson dodecamer. We found that the ethidium ligand binds mainly stacked on, or intercalated between, the terminal base pairs of the DNA with little to no interaction with the inner base pairs. As the intercalation at the terminal CpG steps is relatively rapid, the resultant DNA unwinding, rigidification, and increased stability of the internal base pair steps inhibits further intercalation. In order to reduce these interactions and to provide a larger groove space, a second 18-mer DNA duplex system with the sequence d(GCATGAACGAACGAACGC) was tested. We computed molecular dynamics simulations for 20 independent replicas with this sequence, each with ∼27 μs of sampling time. Results show several spontaneous intercalation and base-pair eversion events that are consistent with experimental observations. The present work suggests that extended MD simulations with modern DNA force fields and optimized simulation codes are allowing the ability to reproduce unbiased intercalation events that we were not able to previously reach due to limits in computing power and the lack of extensively tested force fields and analysis tools.

scholarly journals The model structure of the hammerhead ribozyme formed by RNAs of reciprocal chirality

2020 ◽  
Author(s):  
Eliza Wyszko ◽  
Mariusz Popenda ◽  
Dorota Gudanis ◽  
Joanna Sarzyńska ◽  
Agnieszka Belter ◽  
...  
Keyword(s):  
Hammerhead Ribozyme ◽  
Three Dimensional ◽  
Nuclease Activity ◽  
Base Pairs ◽  
Left Handed ◽  
Low Field ◽  
The Stability ◽  
Dynamics Simulations ◽  
Rna Complexes ◽  
Catalytic Nucleic Acids

RNA-based tools are frequently used to modulate gene expression in living cells. However, the stability and effectiveness of such RNA-based tools is limited by cellular nuclease activity. One way to increase RNA’s resistance to nucleases is to replace its D-ribose backbone with L-ribose isomers. This modification changes chirality of an entire RNA molecule to L-form giving it more chance of survival when introduced into cells. Recently, we have described the activity of left-handed hammerhead ribozyme (L-Rz, L-HH) that can specifically hydrolyze RNA with the opposite chirality at a predetermined location. To understand the structural background of the RNA specific cleavage in a heterochiral complex, we used circular dichroism (CD) and nuclear magnetic resonance (NMR) spectroscopy as well as performed molecular modelling and dynamics simulations of homo- and heterochiral RNA complexes. The active ribozyme-target heterochiral complex showed a mixed chirality as well as low field imino proton NMR signals. We modelled the three dimensional structures of the oligoribonucleotides with their ribozyme counterparts of reciprocal chirality. L- or D-ribozyme formed a stable, homochiral helix 2, and two short double heterochiral helixes 1 and 3 of D- or L-RNA strand thorough irregular Watson-Crick base pairs. The formation of the heterochiral complexes is supported by the result of simulation molecular dynamics. These new observations suggest that L-catalytic nucleic acids can be used as tools in translational biology and diagnostics.

scholarly journals How the water-soluble hemicarcerand incarcerates guests at room temperature decoded with modular simulations

2021 ◽  
Vol 4 (1) ◽  
Author(s):  
Katherine G. McFerrin ◽  
Yuan-Ping Pang
Keyword(s):  
Molecular Dynamics ◽  
Molecular Dynamics Simulations ◽  
Room Temperature ◽  
Model Building ◽  
Three Dimensional ◽  
Building Blocks ◽  
Water Soluble ◽  
Molecular Complexation ◽  
Three Dimensional Models ◽  
Dynamics Simulations

AbstractMolecular dynamics simulations of hemicarcerands and related variants allow the study of constrictive binding and offer insight into the rules of molecular complexation, but are limited because three-dimensional models of hemicarcerands are tedious to build and their atomic charges are complicated to derive. There have been no molecular dynamics simulations of the reported water-soluble hemicarcerand (Octacid4) that explain how Octacid4 encapsulates guests at 298 K and keeps them encapsulated at 298 K in NMR experiments. Herein we report a modular approach to hemicarcerand simulations that simplifies the model building and charge derivation in a manner reminiscent of the approach to protein simulations with truncated amino acids as building blocks. We also report that in aqueous molecular dynamics simulations at 298 K apo Octacid4 adopts two clusters of conformations one of which has an equatorial portal open but the guest-bound Octacid4 adopts one cluster of conformations with all portals closed. These results explain how Octacid4 incarcerates guests at room temperature and suggest that the guest-induced host conformational change that impedes decomplexation is a previously unrecognized conformational characteristic that promotes strong molecular complexation.

scholarly journals Online biophysical predictions for SARS-CoV-2 proteins

2021 ◽  
Vol 22 (1) ◽  
Author(s):  
Luciano Kagami ◽  
Joel Roca-Martínez ◽  
Jose Gavaldá-García ◽  
Pathmanaban Ramasamy ◽  
K. Anton Feenstra ◽  
...  
Keyword(s):  
Protein Sequence ◽  
Three Dimensional ◽  
Dimensional Structure ◽  
Static Structure ◽  
Homologous Proteins ◽  
Structure Based Drug Design ◽  
Protein Protein Interaction ◽  
Link Type ◽  
Dynamics Simulations ◽  
Β Sheet

Abstract Background The SARS-CoV-2 virus, the causative agent of COVID-19, consists of an assembly of proteins that determine its infectious and immunological behavior, as well as its response to therapeutics. Major structural biology efforts on these proteins have already provided essential insights into the mode of action of the virus, as well as avenues for structure-based drug design. However, not all of the SARS-CoV-2 proteins, or regions thereof, have a well-defined three-dimensional structure, and as such might exhibit ambiguous, dynamic behaviour that is not evident from static structure representations, nor from molecular dynamics simulations using these structures. Main We present a website (https://bio2byte.be/sars2/) that provides protein sequence-based predictions of the backbone and side-chain dynamics and conformational propensities of these proteins, as well as derived early folding, disorder, β-sheet aggregation, protein-protein interaction and epitope propensities. These predictions attempt to capture the inherent biophysical propensities encoded in the sequence, rather than context-dependent behaviour such as the final folded state. In addition, we provide the biophysical variation that is observed in homologous proteins, which gives an indication of the limits of their functionally relevant biophysical behaviour. Conclusion The https://bio2byte.be/sars2/ website provides a range of protein sequence-based predictions for 27 SARS-CoV-2 proteins, enabling researchers to form hypotheses about their possible functional modes of action.

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