Energy Landscapes of Hybrid Potentials Based on NMR Data

Abstract

Understanding the structure, topology, and conformational dynamics of proteins is a central tenet of the structure-function paradigm. The NMR hybrid potential, which facilitates the direct incorporation of experimental information into the biomolecualr simulations within the energy landscape framework, is presented. It enhances the simulations of proteins, membrane proteins in particular, in terms of producing experimentally compatible structures and orientations when the atomistic force fields do not necessarily support the native states as the global or low-lying minima. This provides a realistic whilst greatly simplified representation for the solvent or membrane environments surrounding the protein under investigation. The incorporation of NMR structural constraints into basin-hopping via NMR hybrid potentials produced improved structure prediction results, in terms of accu- racy and efficiency, for benchmarking systems trpzip 1 and DP5. Energy landscapes for NMR hybrid potentials were analysed, which justified the improvements, and provided insight and guidance into the setup of hybrid potentials for future studies. In addition to structural features, the topology for membrane proteins was improved during the simulation of transmembrane proteins sarcolipin and phospholamban, achieved by introducing ssNMR orientational constraints in the hybrid potentials. Together, the structural and orientational constraints in the hybrid potential setup proved to be sufficient to represent the environment for membrane proteins, provid- ing an alternative approach for feasible computational studies of membrane proteins, alongside explicit or implicit membranes, and coarse-grained models. Based on this novel approach, the protein E of the SARS-CoV-2 virus was in- vestigated. Our conformational dynamics study revealed the predicted structure for the open-state of the E viroporin in the absence of experimental information, which is an active functional state of E, responsible for selective cation conduction, and release of progeny viruses. The predicted structure and topology for the open-state was further validated by the emerging ssNMR experimental data. The energy land- scape for the E viroporin supported by the hybrid potential was then analysed. The ion conduction mechanism was explained by explicitly constructing the complete calcium conduction pathways, using the NMR hybrid potential and methods in the energy landscape framework. The results presented here provide not only essential insight of the functions of E, but also valuable fundamental knowledge to design antiviral drugs targeting the E virporin, against the CoV-19 pandemic.