Albany 2013: Book of Abstracts
June 11-15 2013
©Adenine Press (2012)
Molecular dynamics approach for DNA duplex thermal stability prediction
Development of new derivatives and analogues of nucleic acids (NA) with precalculated physico-chemical properties is important both in practice and basic research. Unfortunately these studies remain laborious, costly and time-consuming. The in silico research probably could resolve this problem due to significant progress in development of computer software and hardware. The aim of this work is to study a molecular dynamics approach for nucleic acid hybridization enthalpy calculation.
The enthalpies of DNA duplex formation were calculated as a difference of the total internal energy of double- and single-stranded states which were averaged from 10 ns MD trajectory computed with Amber 11 software (UCSF, USA). Computations were performed on NVIDIA GTX580/Intel i7-2600 hardware and resources of Siberian supercomputer center (ICMMG SB RAS). The use of GPU has speeded up the modeling in implicit solvent up to 60 times and up to 30 times in explicit solvent in comparison with the one node of CPU.
To determine optimal parameter set of modeling we have used Dickerson-Drew dodecamer (DDD) 5'-CGCGAATTCGCG-3' with well characterized secondary structure and thermal stability. We have varied force field, temperature, heating protocol, and ion concentration in implicit and explicit solvent, solvent shell radius and compared averaged structures with those experimentally obtained. Using optimal parameters of modeling we have shown that hybridization enthalpy of DDD correlates well with experimental and calculated one nearest neighbor models enthalpies (Lomzov et.al., 2006). The differences were <15% whereas the experimental accuracy is about 10%. To verify the MD predictive ability we have collected database of experimentally determined thermodynamic parameters (enthalpy and entropy) of hybridization of 272 oligodeoxyribonucleotides. The length of oligonucleotides varies from 4 up to 16 base pair (aver. 9 bp), GC-content 0-100% (aver. 57%). The total energy of oligonucleotide or duplex was averaged over 10 000 snapshots of 10 ns trajectories simulated with optimal parameter set. The correlation between the values of hybridization enthalpies obtained experimentally and calculated using MD shown on figure. The RMSD and average error values of calculated and experimental enthalpies were less than 12 and 15%, respectively. The results obtained show that MD modeling allows one to calculate enthalpy of matched DNA duplexes with surprisingly good accuracy.
This research has been supported by RFBR (12-04-31776 mol_a), Contracts (8123, 8535), Integration grant SB RAS (86), and by MCB programs of RAS.
Lomzov, A. A., Pyshnaya, I. A., Ivanova E. M., Pyshnyi, D. V. (2006). Thermodynamic parameters for calculating the stability of complexes of bridged oligonucleotides. Dokl. Bio-chem. Biophys. 409, 211-215.
Institute of Chemical Biology and Fundamental Medicine SB RAS