QM/MM Calculations on Protein–RNA Complexes: Understanding Limitations of Classical MD Simulations and Search for Reliable Cost-Effective QM Methods

Although
atomistic explicit-solvent Molecular Dynamics (MD) is
a popular tool to study protein–RNA recognition, satisfactory
MD description of protein–RNA complexes is not always achieved.
Unfortunately, it is often difficult to separate MD simulation instabilities
primarily caused by the simple point-charge molecular mechanics (MM)
force fields from problems related to the notorious uncertainties
in the starting structures. Herein, we report a series of large-scale
QM/MM calculations on the U1A protein–RNA complex. This experimentally
well-characterized system has an intricate protein–RNA interface,
which is very unstable in MD simulations. The QM/MM calculations identify
several H-bonds poorly described by the MM method and thus indicate
the sources of instabilities of the U1A interface in MD simulations.
The results suggest that advanced QM/MM computations could be used
to indirectly rationalize problems seen in MM-based MD simulations
of protein–RNA complexes. As the most accurate QM method, we
employ the computationally demanding meta-GGA density functional TPSS-D3­(BJ)/def2-TZVP
level of theory. Because considerably faster methods would be needed
to extend sampling and to study even larger protein–RNA interfaces,
a set of low-cost QM/MM methods is compared to the TPSS-D3­(BJ)/def2-TZVP
data. The PBEh-3c and B97-3c density functional composite methods
appear to be suitable for protein–RNA interfaces. In contrast,
HF-3c and the tight-binding Hamiltonians DFTB3-D3 and GFN-xTB perform
unsatisfactorily and do not provide any advantage over the MM description.
These conclusions are supported also by similar analysis of a simple
HutP protein–RNA interface, which is well-described by MD with
the exception of just one H-bond. Some other methodological aspects
of QM/MM calculations on protein–RNA interfaces are discussed.