Structures and Dynamics of DNA Mini-Dumbbells are Force Field Dependent

By Lauren Winkler, Rodrigo Galindo-Murillo, Thomas E. Cheatham III.

Department of Medicinal Chemistry, College of Pharmacy, University of Utah

Resources from the Center for High Performance Computing were used to evaluate the influence of chosen force fields on Molecular Dynamics (MD) simulations of non-duplex DNA structures. 

Flexible nucleic acid structures can be challenging to accurately resolve with currently available experimental structural determination techniques. MD simulations can be implemented to complement experimental techniques and have shown great success in modeling duplex DNA structures. Currently, noncanonical (non-duplex) structures have proven quite challenging to accurately replicate with respect to experimental structures.  These structures are more sensitive to the balances of inter- and intra- molecular forces including charge interactions, hydrogen bonding, stacking contacts, and backbone flexibility, to name a few.  In simulations, the forces are represented as “force fields” and small differences between force fields can lead to large differences in the simulations. In this work, currently available nucleic acid force fields are evaluated using a flexible, yet stable model system: the DNA mini-dumbbell. Prior to MD simulations, NMR re-refinement was accomplished using improved refinement techniques in explicit solvent to yield DNA mini-dumbbell structures that better agree with each other among the newly determined PDB snapshots, with the NMR data itself, as well as the unrestrained simulation data. Starting from newly determined structures, a total aggregate of over 800 µs of production data between 2 DNA mini-dumbbell sequences and 8 force fields was collected to compare to these newly refined structures. The force fields tested spanned from traditional Amber force fields: bsc0, bsc1, OL15, and OL21; to Charmm force fields: Charmm36 and the Drude polarizable force field; as well as force fields from independent developers: Tumuc1 and CuFix/NBFix. The results indicated slight variations not only between the different force fields, but also between the sequences. Surprisingly, many of the recently developed force fields generated structures in good agreement with experiments. Yet, each of the force fields provided a different distribution of potentially anomalous structures. 

To find out more about this project, read the paper in the Journal of Computation and Theoretical Chemistry. 

System Status

Cluster Utilization