dc.contributor.author | Polydoridis, Savvas | en |
dc.contributor.author | Leonidas, Demetres D. | en |
dc.contributor.author | Oikonomakos, Nikos G. | en |
dc.contributor.author | Archontis, Georgios Z. | en |
dc.creator | Polydoridis, Savvas | en |
dc.creator | Leonidas, Demetres D. | en |
dc.creator | Oikonomakos, Nikos G. | en |
dc.creator | Archontis, Georgios Z. | en |
dc.date.accessioned | 2019-12-02T15:32:28Z | |
dc.date.available | 2019-12-02T15:32:28Z | |
dc.date.issued | 2007 | |
dc.identifier.uri | http://gnosis.library.ucy.ac.cy/handle/7/59012 | |
dc.description.abstract | The proteins of the pancreatic ribonuclease A (RNase A) family catalyze the cleavage of the RNA polymer chain. The development of RNase inhibitors is of significant interest, as some of these compounds may have a therapeutic effect in pathological conditions associated with these proteins. The most potent low molecular weight inhibitor of RNase reported to date is the compound 5′-phospho-2′-deoxyuridine-3-pyrophosphate (P→5)-adenosine-3- phosphate (pdUppA-3′-p). The 3′,5′-pyrophosphate group of this compound increases its affinity and introduces structural features which seem to be unique in pyrophosphate-containing ligands bound to RNase A, such as the adoption of a syn conformation by the adenosine base at RNase subsite B 2 and the placement of the 5′-β-phosphate of the adenylate (instead of the α-phosphate) at subsite P1 where the phosphodiester bond cleavage occurs. In this work, we study by multi-ns molecular dynamics simulations the structural properties of RNase A complexes with the ligand pdUppA-3′-p and the related weaker inhibitor dUppA, which lacks the 3′ and 5′ terminal phosphate groups of pdUppA-3′-p. The simulations show that the adenylate 5′-β-phosphate binding position and the adenosine syn orientation constitute robust structural features in both complexes, stabilized by persistent interactions with specific active-site residues of subsites P1 and B2. The simulation structures are used in conjunction with a continuum-electrostatics (Poisson-Boltzmann) model, to evaluate the relative binding affinity of the two complexes. The computed relative affinity of pdUppA-3′-p varies between -7.9 kcal/mol and -2.8 kcal/mol for a range of protein/ligand dielectric constants (εp) 2-20, in good agreement with the experimental value (-3.6 kcal/mol) | en |
dc.description.abstract | the agreement becomes exact with εep = 8. The success of the continuum-electrostatics model suggests that the differences in affinity of the two ligands originate mainly from electrostatic interactions. A residue decomposition of the electrostatic free energies shows that the terminal phosphate groups of pdUppA-3′-p make increased interactions with residues Lys7 and Lys66 of the more remote sites P2 and P0, and His119 of site P1. © 2007 by the Biophysical Society. | en |
dc.source | Biophysical journal | en |
dc.source.uri | https://www.scopus.com/inward/record.uri?eid=2-s2.0-33847768547&doi=10.1529%2fbiophysj.106.093419&partnerID=40&md5=e5e330920ceed7be07efbfc3612f892e | |
dc.subject | Computer Simulation | en |
dc.subject | article | en |
dc.subject | decomposition | en |
dc.subject | unclassified drug | en |
dc.subject | binding affinity | en |
dc.subject | protein interaction | en |
dc.subject | crystal structure | en |
dc.subject | Ligands | en |
dc.subject | catalysis | en |
dc.subject | complex formation | en |
dc.subject | ligand | en |
dc.subject | electricity | en |
dc.subject | hydrogen bond | en |
dc.subject | protein conformation | en |
dc.subject | molecular dynamics | en |
dc.subject | Binding Sites | en |
dc.subject | ribonuclease A | en |
dc.subject | dielectric constant | en |
dc.subject | 5' phospho 2' deoxyuridein 3 pyrophosphate(p-5)adenosine 3 phosphate | en |
dc.subject | Adenosine Monophosphate | en |
dc.subject | Deoxyuracil Nucleotides | en |
dc.subject | dinucleotide | en |
dc.subject | pyrophosphate | en |
dc.subject | ribonuclease inhibitor | en |
dc.subject | Ribonuclease, Pancreatic | en |
dc.title | Recognition of ribonuclease A by 3′-5′-pyrophosphate-linked dinucleotide inhibitors: A molecular dynamics/continuum electrostatics analysis | en |
dc.type | info:eu-repo/semantics/article | |
dc.identifier.doi | 10.1529/biophysj.106.093419 | |
dc.description.volume | 92 | |
dc.description.issue | 5 | |
dc.description.startingpage | 1659 | |
dc.description.endingpage | 1672 | |
dc.author.faculty | Σχολή Θετικών και Εφαρμοσμένων Επιστημών / Faculty of Pure and Applied Sciences | |
dc.author.department | Τμήμα Φυσικής / Department of Physics | |
dc.type.uhtype | Article | en |
dc.description.notes | <p>Cited By :9</p> | en |
dc.source.abbreviation | Biophys.J. | en |
dc.contributor.orcid | Leonidas, Demetres D. [0000-0002-3874-2523] | |
dc.contributor.orcid | Archontis, Georgios Z. [0000-0002-7750-8641] | |
dc.gnosis.orcid | 0000-0002-3874-2523 | |
dc.gnosis.orcid | 0000-0002-7750-8641 | |