Determining the topology of stable protein–DNA complexes

Darcy, Isabel K.; Vázquez, Mariel

doi:10.1042/bst20130004

Cited by 14 publications

(9 citation statements)

References 46 publications

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“…14 It provides the ultimate level of abstraction of many biological processes, such as the open or close of ion channels, the assembly or disassembly of virus capsids, the folding and unfolding of proteins, and the association or dissociation of ligands. 13,[15][16][17][18][19][20][21] However, conventional topology or homology is truly free of metrics or coordinates and thus retains too little geometric information to be practically useful. Persistent homology is a new branch of algebraic topology that embeds multiscale geometric information into topological invariants to achieve the interplay between geometry and topology.…”

Section: Introductionmentioning

confidence: 99%

Integration of element specific persistent homology and machine learning for protein‐ligand binding affinity prediction

Cang

Wei

2017

Numer Methods Biomed Eng

147

199

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Protein-ligand binding is a fundamental biological process that is paramount to many other biological processes, such as signal transduction, metabolic pathways, enzyme construction, cell secretion, and gene expression. Accurate prediction of protein-ligand binding affinities is vital to rational drug design and the understanding of protein-ligand binding and binding induced function. Existing binding affinity prediction methods are inundated with geometric detail and involve excessively high dimensions, which undermines their predictive power for massive binding data. Topology provides the ultimate level of abstraction and thus incurs too much reduction in geometric information. Persistent homology embeds geometric information into topological invariants and bridges the gap between complex geometry and abstract topology. However, it oversimplifies biological information. This work introduces element specific persistent homology (ESPH) or multicomponent persistent homology to retain crucial biological information during topological simplification. The combination of ESPH and machine learning gives rise to a powerful paradigm for macromolecular analysis. Tests on 2 large data sets indicate that the proposed topology-based machine-learning paradigm outperforms other existing methods in protein-ligand binding affinity predictions. ESPH reveals protein-ligand binding mechanism that can not be attained from other conventional techniques. The present approach reveals that protein-ligand hydrophobic interactions are extended to 40Å away from the binding site, which has a significant ramification to drug and protein design.

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Section: Introductionmentioning

confidence: 99%

Integration of element specific persistent homology and machine learning for protein‐ligand binding affinity prediction

Cang

Wei

2017

Numer Methods Biomed Eng

147

199

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“…This example illustrates the importance of local topological changes in addition to global topology in DNA-enzyme interactions. Random cyclization of DNA, enhanced by entangled DNA conditions in tight spaces such as bacteriophage DNA in capsid or site-specific recombination processes, can also lead to the formation of knots in the DNA [reviewed in (Darcy and Vazquez 2013)].…”

Section: Dna Topologymentioning

confidence: 99%

The dynamic interplay between DNA topoisomerases and DNA topology

Seol

Neuman

2016

Biophys Rev

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Topological properties of DNA influence its structure and biochemical interactions. Within the cell DNA topology is constantly in flux. Transcription and other essential processes including DNA replication and repair, alter the topology of the genome, while introducing additional complications associated with DNA knotting and catenation. These topological perturbations are counteracted by the action of topoisomerases, a specialized class of highly conserved and essential enzymes that actively regulate the topological state of the genome. This dynamic interplay among DNA topology, DNA processing enzymes, and DNA topoisomerases, is a pervasive factor that influences DNA metabolism in vivo. Building on the extensive structural and biochemical characterization over the past four decades that established the fundamental mechanistic basis of topoisomerase activity, the unique roles played by DNA topology in modulating and influencing the activity of topoisomerases have begun to be explored. In this review we survey established and emerging DNA topology dependent protein-DNA interactions with a focus on in vitro measurements of the dynamic interplay between DNA topology and topoisomerase activity.

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“…Partly because of this ambiguity, relating enzyme-mediated changes in DNA topology to DNA geometry often requires some assumptions about the geometries of nucleoprotein intermediates in the enzymatic pathway. 11,12 These assumptions can be difficult to confirm independently through measurements in solution; moreover, atomic-resolution crystallographic structures are not always helpful in resolving structural ambiguities because of inherently limited information about conformational dynamics. Thus, nuances such as conformational changes in the context of a cellular environment may not be fully revealed.…”

Section: Introductionmentioning

confidence: 99%

“…A previous topological study of tyrosine recombinases, including Cre, revealed an excess of (+)-noded knotted recombinant DNA products over (-)-noded topologies 29. This excess implies the existence of a productive right-handed recombination intermediate; however, no available crystallographic structure for any of these recombinases with their DNA target12 sites shows significant right-handed chirality. The data presented here provide the first direct evidence for a right-handed recombination intermediate in solution and also support apparent asymmetries in the arrangement of recombination sites observed by…”

mentioning

confidence: 95%

Loop-closure Kinetics Reveal a Stable, Right-handed DNA Intermediate in Cre Recombination

Shoura

Giovan

Vetcher

et al. 2019

Preprint

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In Cre site-specific recombination, the synaptic intermediate is a recombinase homotetramer containing a pair of DNA target sites. The strand-exchange mechanism proceeds via a Holliday-junction (HJ) intermediate; however, the geometry of the DNA segments in the synapse has remained highly controversial. In particular, all crystallographic structures are consistent with an achiral planar Holliday-junction (HJ) structure, whereas topological assays based on Cre-mediated knotting of plasmid DNAs are consistent with a right-handed chiral junction. Here we use the kinetics of loop closure involving closely spaced (131-151 bp), directly repeated loxP sites to investigate the in-aqueo ensemble of conformations for the longest-lived looped DNA intermediate. Fitting the experimental site-spacing dependence of the loop-closure probability, J, to a statistical-mechanical theory of DNA looping provides evidence for substantial out-ofplane HJ distortion. This result unequivocally stands in contrast to the square-planar intermediate geometry determined from crystallographic data for the Cre-loxP system and other int-superfamily recombinases. J measurements carried out with an isomerization-deficient Cre mutant suggest that the apparent geometry of the wild-type complex may result from the temporal averaging of diverse right-handed and achiral structures. Applied to Cre recombinase, and other biological systems, our approach bridges the static pictures provided by crystal structures and the natural dynamics of macromolecules in vivo. This approach thus advances a more comprehensive dynamic analysis of large nucleoprotein structures and their mechanisms.

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Determining the topology of stable protein–DNA complexes

Cited by 14 publications

References 46 publications

Integration of element specific persistent homology and machine learning for protein‐ligand binding affinity prediction

Integration of element specific persistent homology and machine learning for protein‐ligand binding affinity prediction

The dynamic interplay between DNA topoisomerases and DNA topology

Loop-closure Kinetics Reveal a Stable, Right-handed DNA Intermediate in Cre Recombination

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