PROSIT:  Pseudo-Rotational Online Service and Interactive Tool, Applied to a Conformational Survey of Nucleosides and Nucleotides

Sun, Guangyu; Voigt, Johannes H.; Filippov, Igor V.; Márquez, Víctor E.; Nicklaus, Marc C.

doi:10.1021/ci049881+

Cited by 58 publications

(66 citation statements)

References 48 publications

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“…The generated structures were subjected to an all-atom geometry optimization and the geometric characteristics of the optimized minimum energy conformations including bond lengths, valence, and torsion angles as well as hydrogen-bond characteristics (for those showing H bonds) and mutual base arrangements were analyzed. The program PROSIT [19] was used for the analysis of sugar-ring puckering and glycosyl torsions.…”

Section: Methodsmentioning

confidence: 99%

DFT study of polymorphism of the DNA double helix at the level of dinucleoside monophosphates

Poltev

Anisimov²,

Danilov

et al. 2010

Int J of Quantum Chemistry

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ABSTRACT:We apply DFT calculations to deoxydinucleoside monophosphates (dDMPs) which represent minimal fragments of the DNA chain to study the molecular basis of stability of the DNA duplex, the origin of its polymorphism and conformational heterogeneity. In this work, we continue our previous studies of dDMPs where we detected internal energy minima corresponding to the ''classical'' B conformation (BI-form), which is the dominant form in the crystals of oligonucleotide duplexes. We obtained BI local energy minima for all existing base sequences of dDMPs. In the present study, we extend our analysis to other families of DNA conformations, successfully identifying A, BI, and BII energy minima for all dDMP sequences. These conformations demonstrate distinct differences in sugar ring puckering, but similar sequence-dependent base arrangements. Internal energies of BI and BII conformers are close to each other for nearly all the base sequences. The dGpdG, dTpdG, and dCpdA dDMPs slightly favor the BII conformation, which agrees with these sequences being more frequently experimentally encountered in the BII form. We have found BII-like structures of dDMPs for the base sequences both existing in crystals in BII conformation and those not yet encountered in crystals till now. On the other hand, we failed to obtain dDMP energy minima corresponding to the Z family of DNA conformations, thus giving us the ground to conclude that these conformations are stabilized in both crystals and solutions by external factors, presumably by interactions with various components of the media. Overall the accumulated computational data demonstrate that the A, BI, and BII families of DNA conformations originate from the corresponding local energy minimum conformations of dDMPs, thus determining structural stability of a single DNA strand during the processes of unwinding and rewinding of DNA.

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Section: Methodsmentioning

confidence: 99%

DFT study of polymorphism of the DNA double helix at the level of dinucleoside monophosphates

Poltev

Anisimov²,

Danilov

et al. 2010

Int J of Quantum Chemistry

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“…[35] Given the fact that in the crystal structure ((À)-1) and the computer models ((À)-3 and (À)-6) of the enzyme-inhibitor complexes the ligands adopt S-type ribose conformations (P = 1838, 1828, and 1928, respectively), [36] and assuming similar conformational preferences of the bisubstrate inhibitors and the parent 5'-unmodified nucleosides, differences in ribose puckering cannot be a major contributor to the observed dramatic variations in binding affinity between (À)-3 and (À)-6. Rather, differences in solvation between free (À)-1, (À)-3, and (À)-6 may play an important role in determining the measured free enthalpies of binding for the complexes with COMT.…”

Section: In Vitro Biological Activitymentioning

confidence: 99%

Bisubstrate Inhibitors of Catechol O‐Methyltransferase (COMT): the Crucial Role of the Ribose Structural Unit for Inhibitor Binding Affinity

et al. 2006

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Inhibition of the enzyme catechol O-methyltransferase offers a therapeutic handle to regulate the catabolism of catecholamine neurotransmitters, providing valuable assistance in the treatment of CNS disorders such as Parkinson's disease. A series of ribose-modified bisubstrate inhibitors of COMT featuring 2'-deoxy-, 3'-deoxy-, 2'-aminodeoxy-3'-deoxy-, and 2'-deoxy-3'-aminodeoxyribose-derived central moieties and analogues containing the carbocyclic skeleton of the natural product aristeromycin were synthesized and evaluated to investigate the molecular recognition properties of the ribose binding site in the enzyme. Key synthetic intermediates in the ribose-derived series were obtained by deoxygenative [1,2]-hydride shift rearrangement of adenosine derivatives; highlights in the synthesis of carbocyclic aristeromycin analogues include a diastereoselective cyclopropanation step and nucleobase introduction with a modified Mitsunobu protocol. In vitro biological evaluation and kinetic studies revealed dramatic effects of the ribose modification on binding affinity: 3'-deoxygenation of the ribose gave potent inhibitors (IC50 values in the nanomolar range), which stands in sharp contrast to the remarkable decrease in potency observed for 2'-deoxy derivatives (IC50 values in the micromolar range). Aminodeoxy analogues were only weakly active, whereas the change of the tetrahydrofuran skeleton to a carbocycle unexpectedly led to a complete loss of biological activity. These results confirm that the ribose structural unit of the bisubstrate inhibitors of COMT is a key element of molecular recognition and that modifications thereof are delicate and may lead to surprises.

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“…The conformational analysis of ring conformations of carbohydrates molecules in solution relies heavily on deconvoluting NMR scalar 3 J -coupling constants into ring puckering geometries and populations (De Leeuw and Altona 1983; Padrta and Sklenar 2002; Sun et al 2004). In the case of furanoses, interpreting their conformational populations from 3 J -coupling constants typically requires assumptions regarding to the number of states that are present.…”

Section: Introductionmentioning

confidence: 99%

Insights into furanose solution conformations: beyond the two-state model

Wang

Woods

2016

J Biomol NMR

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A two-state model is commonly used for interpreting ring conformations of furanoses based on NMR scalar 3J-coupling constants, with the ring populating relatively narrow distributions in the North and the South of the pseudorotation itinerary. The validity of this simple approach has been questioned, and is examined here in detail employing molecular dynamics (MD) simulations with a new GLYCAM force field parameter set for furanoses. Theoretical 3J-coupling constants derived from unrestrained MD simulations with the new furanose-specific parameters agreed with the experimental coupling constants to within 1 Hz on average. The results confirm that a two state model is a reasonable description for the ring conformation in the majority of methyl furanosides. However, in the case of methyl α-D-arabinofuranoside the ring populates a continuum of states from North to South via the eastern side of the pseudorotational itinerary. Two key properties are responsible for these differences. Firstly, East and West regions in β- and α-anomers, respectively, are destabilized by the absence of the anomeric effect. And, secondly, East or West conformations can be further destabilized by repulsive interactions among vicinal hydroxyl groups and ring oxygen atoms when the vicinal hydroxyl groups are in syn-configurations (such as in ribose and lyxose) more so than when in anti (arabinose, xylose).

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PROSIT: Pseudo-Rotational Online Service and Interactive Tool, Applied to a Conformational Survey of Nucleosides and Nucleotides

Cited by 58 publications

References 48 publications

DFT study of polymorphism of the DNA double helix at the level of dinucleoside monophosphates

DFT study of polymorphism of the DNA double helix at the level of dinucleoside monophosphates

Bisubstrate Inhibitors of Catechol O‐Methyltransferase (COMT): the Crucial Role of the Ribose Structural Unit for Inhibitor Binding Affinity

Insights into furanose solution conformations: beyond the two-state model

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