(360aw) Comparison of Advanced Sampling Techniques for Atomistic Scale RNA Folding

Although some distinguishing features of RNA may be attributed to RNA’s folding, the long time scale of this process is still elusive. This sluggishness can result from alternative configurations with similar free energy to the native ones. A group of tetraloops was studied in our previous work, and misfolded configurations with free energy competitive to correctly folded structures were identified, supported by experimental results. From a technical point of view, parallel-tempering in the well-tempered ensemble combined with well-tempered metadynamics (PTWTE-WTM) showed less simulation time and more reliable results compared to plain parallel-tempering (PT). In this study, we adopted an alternative protocol, namely On- the-fly Probability Enhanced Sampling (OPES) method. Comparing the two different sampling schemes showed that the multithermal-multiumbrella OPES scheme can successfully replace the PTWTE-WTM scheme and is more efficient than the PTWTE-WTM scheme.