QM/MM Calculations on Protein-RNA Complexes: Understanding Limitations of Classical MD Simulations and Search for Reliable Cost-Effective QM Methods
| Authors | |
|---|---|
| Year of publication | 2018 |
| Type | Article in Periodical |
| Magazine / Source | Journal of Chemical Theory and Computation |
| MU Faculty or unit | |
| Citation | |
| Web | https://pubs.acs.org/doi/10.1021/acs.jctc.8b00670 |
| Doi | http://dx.doi.org/10.1021/acs.jctc.8b00670 |
| Keywords | SMALL NUCLEAR RIBONUCLEOPROTEIN; MOLECULAR-DYNAMICS SIMULATIONS; DENSITY-FUNCTIONAL THEORY; L-HISTIDINE LIGAND; RIBOZYME CATALYSIS; FORCE-FIELD; BACKBONE PARAMETERS; CRYSTAL-STRUCTURE; HAIRPIN RIBOZYME; BINDING DOMAIN |
| Description | 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. |
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