Reversible peptide folding in solution by molecular dynamics simulation 1 1Edited by R. Huber

Daura, Xavier; Jaun, Bernhard; Seebàch, Dieter; Gunsteren, Wilfred F. van; Mark, Alan E.

doi:10.1006/jmbi.1998.1885

Cited by 373 publications

(413 citation statements)

References 41 publications

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“…FEN1 was modeled bound to the Rad1 subunit based on previous experimental work (20). The final models were selected after pairwise rmsd clustering analysis of the MD trajectories (31,32), and the structure closest to the centroid of the most populated cluster was chosen as representative for each ternary complex ( Fig. 1 A and B).…”

Section: Resultsmentioning

confidence: 99%

Repair complexes of FEN1 endonuclease, DNA, and Rad9-Hus1-Rad1 are distinguished from their PCNA counterparts by functionally important stability

Querol-Audí

Cheng

et al. 2012

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

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Processivity clamps such as proliferating cell nuclear antigen (PCNA) and the checkpoint sliding clamp Rad9/Rad1/Hus1 (9-1-1) act as versatile scaffolds in the coordinated recruitment of proteins involved in DNA replication, cell-cycle control, and DNA repair. Association and handoff of DNA-editing enzymes, such as flap endonuclease 1 (FEN1), with sliding clamps are key processes in biology, which are incompletely understood from a mechanistic point of view. We have used an integrative computational and experimental approach to define the assemblies of FEN1 with double-flap DNA substrates and either proliferating cell nuclear antigen or the checkpoint sliding clamp 9-1-1. Fully atomistic models of these two ternary complexes were developed and refined through extensive molecular dynamics simulations to expose their conformational dynamics. Clustering analysis revealed the most dominant conformations accessible to the complexes. The cluster centroids were subsequently used in conjunction with single-particle electron microscopy data to obtain a 3D EM reconstruction of the human 9-1-1/FEN1/DNA assembly at 18-Å resolution. Comparing the structures of the complexes revealed key differences in the orientation and interactions of FEN1 and double-flap DNA with the two clamps that are consistent with their respective functions in providing inherent flexibility for lagging strand DNA replication or inherent stability for DNA repair.F lap endonuclease 1 (FEN1) belongs to a class of essential nucleases (the FEN1 5′ nuclease superfamily) present in all domains of life (1). FEN1 catalyzes the endonucleolytic cleavage of bifurcated DNA or RNA structures known as 5′ flaps. These 5′ flaps are generated during lagging strand DNA synthesis or during long-patch base excision repair. The FEN1 substrates are in fact double-flap DNA (dfDNA) with DNA on the opposite side of the 5′ flap, forming a single nucleotide 3′ flap when bound to the enzyme (2, 3). By removing the 5′ ssDNA or RNA flap from such substrates, FEN1 produces a single nicked product that could be sealed by the subsequent action of a DNA ligase (4). Consistent with its crucial role in DNA replication and repair, FEN1 is highly expressed in all proliferative tissues, and its activity is key for the maintenance of genomic integrity (5). FEN1 has been identified as a cancer susceptibility gene, and mutations in it have been linked to a number of genetic diseases, such as EM map myotonic dystrophy, Huntington disease, several ataxias, fragile X syndrome, and cancer (6-10).The nuclease activity of FEN1 can be stimulated by association with processivity clamps such as proliferating cell nuclear antigen (PCNA), which encircle DNA at sites of replication and repair (11)(12)(13). PCNA is a recognized master coordinator of cellular responses to DNA damage and interacts with numerous DNA repair and cell-cycle control proteins. In this capacity, PCNA serves not only as a mobile platform for the attachment of these proteins to DNA but, importantly, plays an active role in the recru...

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Section: Resultsmentioning

confidence: 99%

Repair complexes of FEN1 endonuclease, DNA, and Rad9-Hus1-Rad1 are distinguished from their PCNA counterparts by functionally important stability

Querol-Audí

Cheng

et al. 2012

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

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“…The initial coordinates of the b-peptide were those of the first six residues of the NMR structure of the b-heptapeptide H-b-HVal-b-HAla-b-HLeu-(S,S)-b-HAla(aMe)-b-HVal-b-HAla-b-HLeu-OH. 12,13,14 In both cases, all residues were converted to either Ala (a-peptide) or b-HAla (b-peptide) by removing any atoms not present in an Ala or b-HAla residue. The coordinates of the nitrogen of the subsequent residue were used as initial coordinates of the second oxygen of the terminal carboxylic acid group.…”

Section: Molecular Systems and Simulationsmentioning

confidence: 99%

A comparison of the different helices adopted by α‐ and β‐peptides suggests different reasons for their stability

Allison¹,

Müller²,

Gunsteren³

2010

Protein Science

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The right-handed a-helix is the dominant helical fold of a-peptides, whereas the lefthanded 3 14 -helix is the dominant helical fold of b-peptides. Using molecular dynamics simulations, the properties of a-helical a-peptides and 3 14 -helical b-peptides with different C-terminal protonation states and in the solvents water and methanol are compared. The observed energetic and entropic differences can be traced to differences in the polarity of the solvent-accessible surface area and, in particular, the solute dipole moments, suggesting different reasons for their stability.

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“…It has been previously shown that this peptide reversibly folds on a 10-100 ns time scale in MD simulations. 27,28 In this work we examine in detail a range of different factors effecting T-REMD simulations. We directly compare the rate of convergence and the computational efficiency of such simulations to standard MD simulations and consider whether the T-REMD simulations in practice yield the same thermodynamic properties and conformational sampling as standard MD in explicit solvent.…”

Section: Introductionmentioning

confidence: 99%

Convergence and sampling efficiency in replica exchange simulations of peptide folding in explicit solvent

Periole

Mark

2007

The Journal of Chemical Physics

126

160

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Replica exchange methods (REMs) are increasingly used to improve sampling in molecular dynamics (MD) simulations of biomolecular systems. However, despite having been shown to be very effective on model systems, the application of REM in complex systems such as for the simulation of protein and peptide folding in explicit solvent has not been objectively tested in detail. Here we present a comparison of conventional MD and temperature replica exchange MD (T-REMD) simulations of a β-heptapeptide in explicit solvent. This system has previously been shown to undergo reversible folding on the time scales accessible to MD simulation and thus allows a direct one-to-one comparison of efficiency. The primary properties compared are the free energy of folding and the relative populations of different conformers as a function of temperature. It is found that to achieve a similar degree of precision T-REMD simulations starting from a random set of initial configurations were approximately an order of magnitude more computationally efficient than a single 800ns conventional MD simulation for this system at the lowest temperature investigated (275K). However, whereas it was found that T-REMD simulations are more than four times more efficient than multiple independent MD simulations at one temperature (300K) the actual increase in conformation sampling was only twofold. The overall gain in efficiency using REMD resulted primarily from the ordering of different conformational states over temperature, as opposed to a large increase of conformational sampling. It is also shown that in this system exchanges are accepted primarily based on (random) fluctuations within the solvent and are not strongly correlated with the instantaneous peptide conformation raising questions in regard to the efficiency of T-REMD in larger systems.

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Reversible peptide folding in solution by molecular dynamics simulation 1 1Edited by R. Huber

Cited by 373 publications

References 41 publications

Repair complexes of FEN1 endonuclease, DNA, and Rad9-Hus1-Rad1 are distinguished from their PCNA counterparts by functionally important stability

Repair complexes of FEN1 endonuclease, DNA, and Rad9-Hus1-Rad1 are distinguished from their PCNA counterparts by functionally important stability

A comparison of the different helices adopted by α‐ and β‐peptides suggests different reasons for their stability

Convergence and sampling efficiency in replica exchange simulations of peptide folding in explicit solvent

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