Limits...
Effects of Restrained Sampling Space and Nonplanar Amino Groups on Free-Energy Predictions for RNA with Imino and Sheared Tandem GA Base Pairs Flanked by GC, CG, iGiC or iCiG Base Pairs.

Yildirim I, Stern HA, Sponer J, Spackova N, Turner DH - J Chem Theory Comput (2009)

Bottom Line: Restraining the structures with hydrogen bond restraints did not improve the predictions.The calculations using positional restraints and a nonplanar amino group reproduce the signs of DeltaG degrees from the experimental results and are, thus, capable of providing useful qualitative insights complementing the NMR experiments.The results suggest that a better description of the backbone is key to reproducing the experimental free energy results with computational free energy predictions.

View Article: PubMed Central - PubMed

Affiliation: Department of Physics and Astronomy, Department of Chemistry and Department of Pediatrics, University of Rochester, Rochester, New York, 14627, and Institute of Biophysics, Academy of Sciences of the Czech Republic, v.v.i., Královopolská 135, 61265 Brno, Czech Republic.

ABSTRACT
Guanine-adenine (GA) base pairs play important roles in determining the structure, dynamics, and stability of RNA. In RNA internal loops, GA base pairs often occur in tandem arrangements and their structure is context and sequence dependent. Calculations reported here test the thermodynamic integration (TI) approach with the amber99 force field by comparing computational predictions of free energy differences with the free energy differences expected on the basis of NMR determined structures of the RNA motifs (5'-GCGGACGC-3')(2), (5'-GCiGGAiCGC-3')(2), (5'-GGCGAGCC-3')(2), and (5'-GGiCGAiGCC-3')(2). Here, iG and iC denote isoguanosine and isocytidine, which have amino and carbonyl groups transposed relative to guanosine and cytidine. The NMR structures show that the GA base pairs adopt either imino (cis Watson-Crick/Watson-Crick A-G) or sheared (trans Hoogsteen/Sugar edge A-G) conformations depending on the identity and orientation of the adjacent base pair. A new mixing function for the TI method is developed that allows alchemical transitions in which atoms can disappear in both the initial and final states. Unrestrained calculations gave DeltaG degrees values 2-4 kcal/mol different from expectations based on NMR data. Restraining the structures with hydrogen bond restraints did not improve the predictions. Agreement with NMR data was improved by 0.7 to 1.5 kcal/mol, however, when structures were restrained with weak positional restraints to sample around the experimentally determined NMR structures. The amber99 force field was modified to partially include pyramidalization effects of the unpaired amino group of guanosine in imino GA base pairs. This provided little or no improvement in comparisons with experiment. The marginal improvement is observed when the structure has potential cross-strand out-of-plane hydrogen bonding with the G amino group. The calculations using positional restraints and a nonplanar amino group reproduce the signs of DeltaG degrees from the experimental results and are, thus, capable of providing useful qualitative insights complementing the NMR experiments. Decomposition of the terms in the calculations reveals that the dominant terms are from electrostatic and interstrand interactions other than hydrogen bonds in the base pairs. The results suggest that a better description of the backbone is key to reproducing the experimental free energy results with computational free energy predictions.

No MeSH data available.


Related in: MedlinePlus

Thermodynamic cycle for GGAC → iGGAiC transformation. Structures in red are observed by NMR26,30 so that ΔG1 − ΔG4 is positive. PDB IDs of (5′GCGGACGC3′)2 and (5′GCiGGAiCGC3′)2 are 1MIS and 2O81, respectively.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
getmorefigures.php?uid=PMC2807739&req=5

fig3: Thermodynamic cycle for GGAC → iGGAiC transformation. Structures in red are observed by NMR26,30 so that ΔG1 − ΔG4 is positive. PDB IDs of (5′GCGGACGC3′)2 and (5′GCiGGAiCGC3′)2 are 1MIS and 2O81, respectively.

Mentions: Here, the sequence dependence of hydrogen-bonding patterns in GA pairs flanked by GC, CG, iGiC, or iCiG pairs is investigated with thermodynamic integration (TI)(29) calculations, which may be used to estimate free energy differences. NMR structures25,26,30 show that the hydrogen-bonding patterns in tandem GA pairs change when the amino and carbonyl groups on flanking GC pairs are transposed to give flanking iGiC pairs (Figures 1and 2). We use explicit solvent MD combined with TI to calculate ΔG°2 and ΔG°3 for the alchemical steps in the thermodynamic cycles shown in Figures 3 and 4. In both cycles


Effects of Restrained Sampling Space and Nonplanar Amino Groups on Free-Energy Predictions for RNA with Imino and Sheared Tandem GA Base Pairs Flanked by GC, CG, iGiC or iCiG Base Pairs.

Yildirim I, Stern HA, Sponer J, Spackova N, Turner DH - J Chem Theory Comput (2009)

Thermodynamic cycle for GGAC → iGGAiC transformation. Structures in red are observed by NMR26,30 so that ΔG1 − ΔG4 is positive. PDB IDs of (5′GCGGACGC3′)2 and (5′GCiGGAiCGC3′)2 are 1MIS and 2O81, respectively.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC2807739&req=5

fig3: Thermodynamic cycle for GGAC → iGGAiC transformation. Structures in red are observed by NMR26,30 so that ΔG1 − ΔG4 is positive. PDB IDs of (5′GCGGACGC3′)2 and (5′GCiGGAiCGC3′)2 are 1MIS and 2O81, respectively.
Mentions: Here, the sequence dependence of hydrogen-bonding patterns in GA pairs flanked by GC, CG, iGiC, or iCiG pairs is investigated with thermodynamic integration (TI)(29) calculations, which may be used to estimate free energy differences. NMR structures25,26,30 show that the hydrogen-bonding patterns in tandem GA pairs change when the amino and carbonyl groups on flanking GC pairs are transposed to give flanking iGiC pairs (Figures 1and 2). We use explicit solvent MD combined with TI to calculate ΔG°2 and ΔG°3 for the alchemical steps in the thermodynamic cycles shown in Figures 3 and 4. In both cycles

Bottom Line: Restraining the structures with hydrogen bond restraints did not improve the predictions.The calculations using positional restraints and a nonplanar amino group reproduce the signs of DeltaG degrees from the experimental results and are, thus, capable of providing useful qualitative insights complementing the NMR experiments.The results suggest that a better description of the backbone is key to reproducing the experimental free energy results with computational free energy predictions.

View Article: PubMed Central - PubMed

Affiliation: Department of Physics and Astronomy, Department of Chemistry and Department of Pediatrics, University of Rochester, Rochester, New York, 14627, and Institute of Biophysics, Academy of Sciences of the Czech Republic, v.v.i., Královopolská 135, 61265 Brno, Czech Republic.

ABSTRACT
Guanine-adenine (GA) base pairs play important roles in determining the structure, dynamics, and stability of RNA. In RNA internal loops, GA base pairs often occur in tandem arrangements and their structure is context and sequence dependent. Calculations reported here test the thermodynamic integration (TI) approach with the amber99 force field by comparing computational predictions of free energy differences with the free energy differences expected on the basis of NMR determined structures of the RNA motifs (5'-GCGGACGC-3')(2), (5'-GCiGGAiCGC-3')(2), (5'-GGCGAGCC-3')(2), and (5'-GGiCGAiGCC-3')(2). Here, iG and iC denote isoguanosine and isocytidine, which have amino and carbonyl groups transposed relative to guanosine and cytidine. The NMR structures show that the GA base pairs adopt either imino (cis Watson-Crick/Watson-Crick A-G) or sheared (trans Hoogsteen/Sugar edge A-G) conformations depending on the identity and orientation of the adjacent base pair. A new mixing function for the TI method is developed that allows alchemical transitions in which atoms can disappear in both the initial and final states. Unrestrained calculations gave DeltaG degrees values 2-4 kcal/mol different from expectations based on NMR data. Restraining the structures with hydrogen bond restraints did not improve the predictions. Agreement with NMR data was improved by 0.7 to 1.5 kcal/mol, however, when structures were restrained with weak positional restraints to sample around the experimentally determined NMR structures. The amber99 force field was modified to partially include pyramidalization effects of the unpaired amino group of guanosine in imino GA base pairs. This provided little or no improvement in comparisons with experiment. The marginal improvement is observed when the structure has potential cross-strand out-of-plane hydrogen bonding with the G amino group. The calculations using positional restraints and a nonplanar amino group reproduce the signs of DeltaG degrees from the experimental results and are, thus, capable of providing useful qualitative insights complementing the NMR experiments. Decomposition of the terms in the calculations reveals that the dominant terms are from electrostatic and interstrand interactions other than hydrogen bonds in the base pairs. The results suggest that a better description of the backbone is key to reproducing the experimental free energy results with computational free energy predictions.

No MeSH data available.


Related in: MedlinePlus