MiMiC currently supports using CPMD as the main MD driver and for calculating subsystem contributions it has interfaces to CPMD and GROMACS. Using the currently supported programs it is possible to run electrostatic-embedding QM/MM MD simulations where CPMD can be used as the QM engine and GROMACS as the MM engine. MiMiC also supports using the PLUMED library for performing enhanced-sampling QM/MM MD simulations.
The MiMiC-based QM/MM implementation has displayed strong scalability well beyond ten thousand cores in a single QM/MM simulation while maintaining an overall parallel efficiency of at least 70%. 2
MiMiC-based QM/MM MD simulations combined with metadynamics have been successfully applied to investigate complex biochemical processes. Below are some examples.
Molecular basis of CLC antiporter inhibition by fluoride
CLC channels and transporters conduct or transport various kinds of anions, with the exception of fluoride, which acts as an effective inhibitor. This study identified the high affinity of both F− and E148 for protons as the basis of the transport inhibition of the CLC anion/proton exchangers from E. coli. 3
Sub-nanosecond QM/MM simulations of the E. coli anion/proton exchanger ClC-ec1 showed that fluoride binds incoming protons within the selectivity filter, with excess protons shared with the gating glutamate E148. Depending on E148 conformation, the competition for the proton can involve either a direct F−/E148 interaction or the modulation of water molecules bridging the two anions. The direct interaction locks E148 in a conformation that does not allow for proton transport, and thus inhibits protein function.
Mechanisms underlying proton release in CLC-type F−/H+ antiporters
The CLC family of anion channels and transporters includes Cl−/H+ exchangers (blocked by F−) and F−/H+ exchangers (or CLCFs). CLCFs contain a glutamate (E318) in the central anion-binding site that is absent in CLC Cl−/H+ exchangers. The X-ray structure of the protein from Enterococcus casseliflavus (CLCF-eca) shows that E318 tightly binds to F− when the gating glutamate (E118; highly conserved in the CLC family) faces the extracellular medium. This study illustrated how glutamate insertion into the central anion-binding site of CLCF-eca permits the release of H+ to the cytosol as HF, thus enabling a net 1:1 F−/H+ stoichiometry. 4
Classical and MiMiC-based QM/MM metadynamics simulations were used to investigate proton transfer and release by CLCF-eca. Results show that after up to down movement of protonated E118, both glutamates combine with F− to form a triad, from which protons and F− anions are released as HF.