Adaptive Partitioning QM/MM for Molecular Dynamics Simulations: 6. Proton Transport through a Biological Channel

Abstract

Adaptive quantum-mechanics/molecular-mechanics (QM/ MM) dynamics simulations feature on-the-fly reclassification of atoms as QM or MM continuously and smoothly as trajectories are propagated. This allows one to use small, mobile QM subsystems, the contents of which are dynamically updated as needed. In this work, we report the first adaptive QM/MM simulations of H + transfer through a biological channel, in particular, the protein EcCLC, a chloride channel (CLC) Cl − /H + antiporter derived from E. coli. To this end, the H + indicator previously formulated for approximating the location of an excess H + in bulk water was extended to include Cl − ions and carboxyl groups as H + donors/acceptors. Furthermore, when setting up buffer groups, a new "sushi-roll" scheme was employed to group multiple water molecules, ions, and titratable residues along the onedimensional channel for adaptive partitions. Our simulations reveal that the H + relay path, which consists of water molecules in the pore, a bound Cl − ion at the central binding site (Cl − cen ) of the protein, and the external gating residue E148, exhibits certain mobility within the channel. A two-stage journey of H + migration was observed: the H + moves toward Cl − cen and is then shared between Cl − cen and nearby water molecules in the first stage and departs from Cl − cen via nearly concerted transfer to protonate E148 in the second stage. Most of the simulated trajectories show the bound Cl − ion in the channel to be transiently protonated, a possibility that was previously suggested by experiments and computations. Comparisons with conventional QM/MM simulations revealed that both adaptive and conventional treatments yield similar qualitative pictures. This work demonstrates the feasibility of adaptive QM/MM in the simulations of H + migration through biological channels.

A CLC-ec1 mutant reveals global conformational change and suggests a unifying mechanism for the CLC Cl–/H+ transport cycle

“…In addition, the proposal is consistent with MD simulations that show the Glu ex /Glu in doubly protonated state is highly populated (Mayes et al, 2018) and can favor formation of water pathways under certain conditions (Ko and Jo, 2010). Nevertheless, simulations with glutamate side chains in the QQQ conformational state, together with explicit evaluation of H + transport (Wang et al, 2018;Duster et al, 2019), are needed to elaborate details of the H + -transfer steps. In addition, multiscale modeling can expand the picture to include multiple pathways that are likely to occur (Mayes et al, 2018).…”

Extending scaled-interaction adaptive-partitioning QM/MM to covalently bonded systems

“…Besides, AP-QM/MM methods with multiple QM calculations may contain partitions that lead to ill-defined QM calculations, especially when treating covalently bonded systems. It is therefore worthwhile to continue developing SISPA-like methods, even though there have been significant advancements in reducing the number of QM calculations in AP-QM/MM for specific systems 12,13 .…”

“…QM/MM methods partition the system into QM and MM subsystems corresponding to the active and the environmental regions. Such a partition is predetermined in regular QM/MM, which is unfavorable when active regions are not stationary or liable to change during the simulation, such as in solution systems [8][9][10] or transport processes [11][12][13] . Adaptivepartitioning (AP) QM/MM 6,7,[14][15][16][17][18][19][20][21][22][23] addresses this problem by allowing the partitioning of the system to change during the simulation.…”

“…The computational cost of PAP becomes prohibitively high when there are more than a few buffer atoms due to the high number of QM calculations. One can group atoms into fragments to reduce the number of partitions in some cases, such as treating solute molecules 17 or different sections of a biological channel 12 as a whole instead of as individual atoms. This needs a thorough understanding of the system under study, and a general grouping scheme that retains the key characteristics of the original system is yet to be found.…”

Quantitative Analysis and Correction of Quantum Mechanics/Molecular Mechanics Boundary Artifacts in Adaptive QM/MM Methods

“…Moreover, the proper form of the correction potential is not obvious for anisotropic system such as the gas-liquid interface, biomolecular surface/binding pocket, although there exist increasing demands of multi-scale simulations in practical applications. [31][32][33][34] On the QM side, there is considerable interest and efforts to improve approximate QM methods to achieve a good trade-off with computational efficiency. 20,[35][36][37][38] On the MM side, significant efforts have been made to develop polarizable models, [39][40][41][42] including in QM/MM simulations.…”