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Statements

Subject Item
n2:RIV%2F00216208%3A11320%2F14%3A10287783%21RIV15-MSM-11320___
rdf:type
skos:Concept n10:Vysledek
rdfs:seeAlso
http://link.springer.com/article/10.1007%2Fs00894-014-2123-x
dcterms:description
The capability of current MD simulations to be used as a tool in rational design of agonists of medically interesting enzyme RNase L was tested. Dimerization and enzymatic activity of RNase L is stimulated by 2',5'-linked oligoadenylates (pA(25)A(25)A; 2-5A). First, it was necessary to ensure that a complex of monomeric human RNase L and 25A was stable in MD simulations. It turned out that Glu131 had to be protonated. The non-protonated Glu131 caused dissociation of 2-5A from RNase L. Because of the atypical 2'-5' internucleotide linkages and a specific spatial arrangement of the 25A trimer, when a single molecule carries all possible conformers of the glycosidic torsion angle, several versions of the AMBER force field were tested. One that best maintained functionally important interactions of 25A and RNase L was selected for subsequent MD simulations. Furthermore, we wonder whether powerful GPUs are able to produce MD trajectories long enough to convincingly demonstrate effects of subtle perturbations of interactions between 25A and RNase L. Detrimental impacts of various point mutations of RNase L (R155A, F126A, W60A, K89A) on 2-5A binding were observed on a time scale of 200 ns. Finally, 2-5A analogues with a bridged 3'-O,4'-C-alkylene linkage (B) introduced into the adenosine units (A) were used to assess ability of MD simulations to distinguish on the time scale of hundreds of nanoseconds between agonists of RNase L (pA(25)A(25)B, pB(25)A(25)A, pB(25)A(25)B) and inactive analogs (pA(25)B(25)A, pA(25)B(25)B, pB(25)B(25)A, pB(25)B(25)B). Agonists were potently bound to RNase L during 200 ns MD runs. For inactive 2-5A analogs, by contrast, significant disruptions of their interactions with RNase L already within 100 ns MD runs were found. The capability of current MD simulations to be used as a tool in rational design of agonists of medically interesting enzyme RNase L was tested. Dimerization and enzymatic activity of RNase L is stimulated by 2',5'-linked oligoadenylates (pA(25)A(25)A; 2-5A). First, it was necessary to ensure that a complex of monomeric human RNase L and 25A was stable in MD simulations. It turned out that Glu131 had to be protonated. The non-protonated Glu131 caused dissociation of 2-5A from RNase L. Because of the atypical 2'-5' internucleotide linkages and a specific spatial arrangement of the 25A trimer, when a single molecule carries all possible conformers of the glycosidic torsion angle, several versions of the AMBER force field were tested. One that best maintained functionally important interactions of 25A and RNase L was selected for subsequent MD simulations. Furthermore, we wonder whether powerful GPUs are able to produce MD trajectories long enough to convincingly demonstrate effects of subtle perturbations of interactions between 25A and RNase L. Detrimental impacts of various point mutations of RNase L (R155A, F126A, W60A, K89A) on 2-5A binding were observed on a time scale of 200 ns. Finally, 2-5A analogues with a bridged 3'-O,4'-C-alkylene linkage (B) introduced into the adenosine units (A) were used to assess ability of MD simulations to distinguish on the time scale of hundreds of nanoseconds between agonists of RNase L (pA(25)A(25)B, pB(25)A(25)A, pB(25)A(25)B) and inactive analogs (pA(25)B(25)A, pA(25)B(25)B, pB(25)B(25)A, pB(25)B(25)B). Agonists were potently bound to RNase L during 200 ns MD runs. For inactive 2-5A analogs, by contrast, significant disruptions of their interactions with RNase L already within 100 ns MD runs were found.
dcterms:title
Recognition of 2 ',5 '-linked oligoadenylates by human ribonuclease L: molecular dynamics study Recognition of 2 ',5 '-linked oligoadenylates by human ribonuclease L: molecular dynamics study
skos:prefLabel
Recognition of 2 ',5 '-linked oligoadenylates by human ribonuclease L: molecular dynamics study Recognition of 2 ',5 '-linked oligoadenylates by human ribonuclease L: molecular dynamics study
skos:notation
RIV/00216208:11320/14:10287783!RIV15-MSM-11320___
n3:aktivita
n15:S n15:P n15:I
n3:aktivity
I, P(GA13-26526S), S
n3:cisloPeriodika
20
n3:dodaniDat
n8:2015
n3:domaciTvurceVysledku
n16:2727366 n16:7768486
n3:druhVysledku
n12:J
n3:duvernostUdaju
n18:S
n3:entitaPredkladatele
n11:predkladatel
n3:idSjednocenehoVysledku
41608
n3:idVysledku
RIV/00216208:11320/14:10287783
n3:jazykVysledku
n13:eng
n3:klicovaSlova
RNase L; NAMD; Molecular dynamics; 2 ',5 ' oligoadenylate; Force field; Ankyrin; ACEMD
n3:klicoveSlovo
n4:NAMD n4:Ankyrin n4:5%20%27%20oligoadenylate n4:Molecular%20dynamics n4:RNase%20L n4:2%20%27 n4:ACEMD n4:Force%20field
n3:kodStatuVydavatele
DE - Spolková republika Německo
n3:kontrolniKodProRIV
[9292867053A8]
n3:nazevZdroje
Journal of Molecular Modeling
n3:obor
n20:BO
n3:pocetDomacichTvurcuVysledku
2
n3:pocetTvurcuVysledku
2
n3:projekt
n19:GA13-26526S
n3:rokUplatneniVysledku
n8:2014
n3:svazekPeriodika
2014
n3:tvurceVysledku
Barvík, Ivan Maláč, Kamil
n3:wos
000334934900033
s:issn
1610-2940
s:numberOfPages
19
n17:doi
10.1007/s00894-014-2123-x
n5:organizacniJednotka
11320