Free energy calculation of modified base-pair formation in explicit solvent: A predictive model

被引:44
作者
Vendeix, Franck A. P. [1 ]
Munoz, Antonio M. [1 ]
Agris, Paul F. [1 ]
机构
[1] N Carolina State Univ, Dept Mol & Struct Biochem, Raleigh, NC 27695 USA
基金
美国国家科学基金会; 美国国家卫生研究院;
关键词
modified nucleosides; base pairs in water; wobble recognition; refined molecular dynamics simulation; NEAREST-NEIGHBOR THERMODYNAMICS; MOLECULAR-DYNAMICS SIMULATIONS; HISTOGRAM ANALYSIS METHOD; TRANSFER-RNA; MODIFIED NUCLEOSIDES; POTENTIAL FUNCTIONS; B-DNA; HYPERMODIFIED NUCLEOSIDES; WOBBLE HYPOTHESIS; ESCHERICHIA-COLI;
D O I
10.1261/rna.1734309
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
The maturation of RNAs includes site-specific post-transcriptional modifications that contribute significantly to hydrogen bond formation within RNA and between different RNAs, especially in formation of mismatch base pairs. Thus, an understanding of the geometry and strength of the base-pairing of modified ribonucleoside 5'-monophosphates, previously not defined, is applicable to investigations of RNA structure and function and of the design of novel RNAs. The geometry and free energies of base-pairings were calculated in aqueous solution under neutral conditions with AMBER force fields and molecular dynamics simulations (MDSs). For example, unmodified uridines were observed to bind to uridine and cytidine with significant stability, but the ribose C1'-C1' distances were far short (similar to 8.9 angstrom) of distances observed for canonical A-form RNA helices. In contrast, 5-oxyacetic acid uridine, known to bind adenosine, wobble to guanosine, and form mismatch base pairs with uridine and cytidine, bound adenosine and guanosine with geometries and energies comparable to an unmodified uridine. However, the 5-oxyacetic acid uridine base paired to uridine and cytidine with a C1'-C1' distance comparable to that of an A-form helix, similar to 11 angstrom, when a H2O molecule migrated between and stably hydrogen bonded to both bases. Even in formation of canonical base pairs, intermediate structures with a second energy minimum consisted of transient H2O molecules forming hydrogen bonded bridges between the two bases. Thus, MDS is predictive of the effects of modifications, H2O molecule intervention in the formation of base-pair geometry, and energies that are important for native RNA structure and function.
引用
收藏
页码:2278 / 2287
页数:10
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