Simulation analysis of formycin 5?-monophosphate analog substrates in the ricin A-chain active site

Olson, Mark A.; Scovill, John P.; Hack, Dallas C.

doi:10.1007/bf00124454

Cited by 4 publications

(8 citation statements)

References 34 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Chemical formulas for PTA and FMP are illustrated in Fig. 1, b and c, with hydrogens added according to the suggested PTA structure (Yan et al, 1997(Yan et al, , 1998 and from previous modeling calculations of FMP (Olson et al, 1995). The phosphate group of FMP was modeled either as a monoanion or dianion.…”

Section: Methodsmentioning

confidence: 99%

“…The FMP binding free energy was calculated for three different structures, where the first two used the x-ray crystallographic complex (Monzingo and Robertus, 1992) and modeled the phosphate group as a monoanion and dianion. The third structure was taken from a previously reported MD simulation of the dianion ligand with RTA (Olson et al, 1995).…”

Section: Binding Free Energies For Small Ligandsmentioning

confidence: 99%

See 1 more Smart Citation

Free Energy Determinants of Binding the rRNA Substrate and Small Ligands to Ricin A-Chain

Olson

Cuff

1999

Biophysical Journal

Self Cite

View full text Add to dashboard Cite

A continuum model is provided of the free energy terms that contribute to the molecular association of ricin A-chain (RTA) with the rRNA substrate and several small ligands. The model for RTA interactions with the RNA was taken from a previously proposed complex containing a 29-mer oligonucleotide hairpin (. Proteins 27:80-95), and models for the ligands were constructed from x-ray crystallographic structures. The calculated absolute free energies of complex formation for the RTA-RNA assembly and several single-residue substitutions are in good agreement with experimental data, given the approximations of evaluating the strain energy and conformational entropy. The free energy terms were found to resemble those of protein-protein complexes, with the net unfavorable electrostatic contribution offset by the favorable nonspecific hydrophobic effect. Decomposition of the RTA-RNA binding free energy into individual contributions revealed the electrostatic "hot" spots arising from charge-charge complementarity of the interfacial arginines with the RNA phosphate backbone. Base interactions of the GAGA loop structure dominate the hydrophobic complementarity. A linear-scaling model was parametrized for evaluating the binding of small ligands against the rRNA substrate and illustrates the free energy determinant required for designing specific RTA inhibitors.

show abstract

Section: Methodsmentioning

confidence: 99%

Section: Binding Free Energies For Small Ligandsmentioning

confidence: 99%

Free Energy Determinants of Binding the rRNA Substrate and Small Ligands to Ricin A-Chain

Olson

Cuff

1999

Biophysical Journal

Self Cite

View full text Add to dashboard Cite

show abstract

“…The binding of the guanosine moiety of ApG fails to mimic and block access to both specific and nonspecific interactions of the two larger molecules. Similarly, the binding of formycin monophosphate 11,21 lacks sufficient conformational mimicry to block substrate binding, although the formycin ring exhibits greater binding affinity than adenine, due to the formation of an extra hydrogen bond. Clearly, a higher affinity for only the adenine binding pocket is insufficient to inactivate ricin.…”

Section: Substrate Binding Determinantmentioning

confidence: 99%

“…Because of the structural complexities and limitations encountered in obtaining cocrystal structures, theoretical studies of the interaction of the RTA molecule with nucleotides may be of great assistance in the interpretation of biophysical data, as well as the exploration of conserved RNA-binding motifs for the RIP family. Preliminary modeling studies of the RTA complex with FMP have been reported 21 using the molecular dynamics (MD) simulation method. These studies showed the MD results to agree with the x-ray crystal structure in reproducing an overall conformational binding mode.…”

Section: Introductionmentioning

confidence: 99%

“…The simulation model exhibited, however, significant differences in the location and binding of the phosphoryl group, and suggested a marked decrease in binding of FMP if the phosphoryl group were to be removed. The underlying binding thermodynamics and structural interaction energies of the FMP binding mode were also calculated 21 for several small structural analogues by using MD free-energy simulation methods. From the MD simulation results together with those of crystallographic studies, it remains an open question as to the extent of conformational and energetic mimicry that exist in binding modes between small nucleotides and the substrate.…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Ricin A-chain structural determinant for binding substrate analogues: A molecular dynamics simulation analysis

Olson¹

1997

Proteins

Self Cite

View full text Add to dashboard Cite

Ricin A-chain is a cytotoxic protein that attacks ribosomes by hydrolyzing a specific adenine base from a highly conserved, single-stranded rRNA hairpin containing the tetraloop sequence GAGA. Molecular-dynamics simulation methods are used to analyze the structural determinant for three substrate analogues bound to the ricin A-chain molecule. Simulations were applied to the binding of the dinucleotide adenyl-3',5'-guanosine employing the x-ray crystal structure of the ricin complex and a modeled CGAGAG hexanucleotide loop taken from the NMR solution structure of a 29-mer oligonucleotide hairpin. A third simulation model is also presented describing a conformational search of the docked 29-mer structure by using a simulated-annealing method. Analysis of the structural interaction energies for each model shows the overall binding dominated by nonspecific interactions, which are mediated by specific arginine contracts from the highly basic region on the protein surface. The tetraloop conformation of the 29-mer was found to make specific interactions with conserved protein residues, in a manner that favored the GAGA sequence. A comparison of the two docked loop conformations with the NMR structure revealed significant positional deviations, suggesting that ricin may use an induced fit mechanism to recognize and bind the rRNA substrate. The conserved Tyr-80 may play an important conformational entropic role in the binding and release of the target adenine in the active site.

show abstract

Recognition and interaction of small rings with the ricin A-chain binding site

et al. 1998

View full text Add to dashboard Cite

Ricin A-chain is an N-glucosidase that attacks ribosomal RNA at a highly conserved adenine residue. Our recent crystallographic studies show that not only adenine and formycin, but also pterin-based rings can bind in the active site of ricin. For a better understanding of the means by which ricin recognizes adenine rings, the geometries and interaction energies were calculated for a number of complexes between ricin and tautomeric modifications of formycin, adenine, pterin, and guanine. These were studied by molecular mechanics, semi-empirical quantum mechanics, and ab initio quantum mechanical methods. The calculations indicate that the formycin ring binds better than adenine and pterin better than formycin, a result that is consistent with the crystallographic data. A tautomer of pterin that is not in the low energy form in either the gas phase or in aqueous solution has the best interaction with the enzyme. The net interaction energy, defined as the interaction energy calculated in vacuo between the receptor and an inhibitor minus the solvation energy of the inhibitor, provides a good prediction of the ability of the inhibitor to bind to the receptor. The results from experimental and molecular modeling work suggest that the ricin binding site is not flexible and may only recognize a limited range of adenine-like rings.

show abstract

Simulation analysis of formycin 5?-monophosphate analog substrates in the ricin A-chain active site

Cited by 4 publications

References 34 publications

Free Energy Determinants of Binding the rRNA Substrate and Small Ligands to Ricin A-Chain

Free Energy Determinants of Binding the rRNA Substrate and Small Ligands to Ricin A-Chain

Ricin A-chain structural determinant for binding substrate analogues: A molecular dynamics simulation analysis

Recognition and interaction of small rings with the ricin A-chain binding site

Contact Info

Product

Resources

About