Structural characteristics of 2'-O-(2-methoxyethyl)-modified nucleic acids from molecular dynamics simulations.
The structure and physical properties of 2'-sugar substituted O -(2-methoxyethyl) (MOE) nucleic acids have been studied using molecular dynamics simulations. Nanosecond simulations on the duplex MOE[CCAACGTTGG]-r[CCAACGUUGG] in aqueous solution have been carried out using the particle mesh Ewald method. Parameters for the simulation have been developed from ab initio calculations on dimethoxyethyl fragments in a manner consistent with the AMBER 4.1 force field database. The simulated duplex is compared with the crystal structure of the self-complementary duplex d[GCGTATMOEACGC]2, which contains a single modification in each strand. Structural details from each sequence have been analyzed to rationalize the stability imparted by substitution with 2'- O -(2-methoxyethyl) side chains. Both duplexes have an A-form structure, as indicated by several parameters, most notably a C3' endo sugar pucker in all residues. The simulated structure maintains a stable A-form geometry throughout the duration of the simulation with an average RMS deviation of 2.0 A from the starting A-form structure. The presence of the 2' substitution appears to lock the sugars in the C3' endo conformation, causing the duplex to adopt a stable A-form geometry. The side chains themselves have a fairly rigid geometry with trans , trans , gauche +/- and trans rotations about the C2'-O2', O2'-CA', CA'-CB' and CB'-OC' bonds respectively.
Department of Medicinal Chemistry and Minnesota Supercomputing Institute, University of Minnesota,308 Harvard Street SE, Minneapolis, MN 55455, USA.
K E
KE
Lind
V
V
Mohan
M
M
Manoharan
D M
DM
Ferguson
D001483:Base Sequence; D004247:DNA / Q000737:chemistry; D008956:Models, Chemical; D008958:Models, Molecular; D015394:Molecular Structure; D009690:Nucleic Acid Conformation; D009696:Nucleic Acids / Q000737:chemistry*; D009838:Oligodeoxyribonucleotides / Q000138:chemical synthesis / Q000737:chemistry; D016376:Oligonucleotides, Antisense / Q000138:chemical synthesis / Q000737:chemistry; D009843:Oligoribonucleotides / Q000138:chemical synthesis / Q000737:chemistry; D012313:RNA / Q000737:chemistry; D013816:Thermodynamics
D009696:Nucleic Acids; D009838:Oligodeoxyribonucleotides; D016376:Oligonucleotides, Antisense; D009843:Oligoribonucleotides; D012313:RNA; D004247:DNA