Quantitative Analysis of QM/MM Boundary Artifacts and Correction in Adaptive QM/MM Simulations.

A quantum chemical treatment of solvation effects using the standard quantum mechanical/molecular mechanical (QM/MM) molecular dynamics simulations is challenging due to QM and MM solvent exchange near the QM solute. To this end, various adaptive QM/MM methods have been proposed; free solvent exchanges are allowed via flexible switching of their identities between QM and MM systems depending on their distances from the QM solute. However, temporal and spatial discontinuities remain in the standard implementations of adaptive QM/MM approaches and continue to hamper stable and accurate dynamics simulations.

Mutational analysis of the conserved carboxylates of anion channelrhodopsin-2 (ACR2) expressed in and their roles in anion transport.

Anion channelrhodopsin-2 (ACR2), a light-gated channel recently identified from the cryptophyte alga , exhibits anion channel activity with exclusive selectivity. In addition to its novel function, ACR2 has become a focus of interest as a powerful tool for optogenetics. Here we combined experimental and computational approaches to investigate the roles of conserved carboxylates on the anion transport activity of ACR2 in membrane.

Improvement of Performance, Stability and Continuity by Modified Size-Consistent Multipartitioning Quantum Mechanical/Molecular Mechanical Method.

For condensed systems, the incorporation of quantum chemical solvent effects into molecular dynamics simulations has been a major concern. To this end, quantum mechanical/molecular mechanical (QM/MM) techniques are popular and powerful options to treat gigantic systems. However, they cannot be directly applied because of temporal and spatial discontinuity problems.

Cation solvation with quantum chemical effects modeled by a size-consistent multi-partitioning quantum mechanics/molecular mechanics method.

In the condensed phase, quantum chemical properties such as many-body effects and intermolecular charge fluctuations are critical determinants of the solvation structure and dynamics. Thus, a quantum mechanical (QM) molecular description is required for both solute and solvent to incorporate these properties. However, it is challenging to conduct molecular dynamics (MD) simulations for condensed systems of sufficient scale when adapting QM potentials.

Origins of Water Molecules in the Photosystem II Crystal Structure.

The cyanobacterial photosystem II (PSII) crystal structure includes more than 1300 water molecules in each monomer unit; however, their precise roles in water oxidation are unclear. To understand the origins of water molecules in the PSII crystal structure, the accessibility of bulk water molecules to channel inner spaces in PSII was investigated using the water-removed PSII structure and molecular dynamics (MD) simulations. The inner space of the channel that proceeds toward the D1-Glu65/D2-Glu312 pair (E65/E312 channel) was entirely filled with water molecules from the bulk region.

Electron transfer pathways in a multiheme cytochrome MtrF.

In MtrF, an outer-membrane multiheme cytochrome, the 10 heme groups are arranged in heme binding domains II and IV along the pseudo- axis, forming the electron transfer (ET) pathways. Previous reports based on molecular dynamics simulations showed that the redox potential () values for the heme pairs located in symmetrical positions in domains II and IV were similar, forming bidirectional ET pathways [Breuer M, Zarzycki P, Blumberger J, Rosso KM (2012) 134(24):9868-9871]. Here, we present the values of the 10 hemes in MtrF, solving the linear Poisson-Boltzmann equation and considering the protonation states of all titratable residues and heme propionic groups.

Structurally conserved channels in cyanobacterial and plant photosystem II.

In the cyanobacterial photosystem II (PSII), the O4-water chain in the D1 and CP43 proteins, a chain of water molecules that are directly H-bonded to O4 of the MnCa cluster, is linked with a channel that connects the protein bulk surface along with a membrane-extrinsic protein subunit, PsbU (O4-PsbU channel). The cyanobacterial PSII structure also shows that the O1 site of the MnCa cluster has a chain of H-bonded water molecules, which is linked with the channel that proceeds toward the bulk surface via PsbU and PsbV (O1-PsbU/V channel). Membrane-extrinsic protein subunits PsbU and PsbV in cyanobacterial PSII are replaced with PsbP and PsbQ in plant PSII.

Active site structure and absorption spectrum of channelrhodopsin-2 wild-type and C128T mutant.

In spite of considerable interest, the active site of channelrhodopsin still lacks a detailed atomistic description, the understanding of which could strongly enhance the development of novel optogenetics tools. We present a computational study combining different state-of-the-art techniques, including hybrid quantum mechanics/molecular mechanics schemes and high-level quantum chemical methods, to properly describe the hydrogen-bonding pattern between the retinal chromophore and its counterions in channelrhodopsin-2 Wild-Type and C128T mutant. Especially, we show by extensive ground state dynamics that the active site, containing a glutamic acid (E123) and a water molecule, is highly dynamic, sampling three different hydrogen-bonding patterns.

An adaptive quantum mechanics/molecular mechanics method for the infrared spectrum of water: incorporation of the quantum effect between solute and solvent.

Quantum effects in solute-solvent interactions, such as the many-body effect and the dipole-induced dipole, are known to be critical factors influencing the infrared spectra of species in the liquid phase. For accurate spectrum evaluation, the surrounding solvent molecules, in addition to the solute of interest, should be treated using a quantum mechanical method. However, conventional quantum mechanics/molecular mechanics (QM/MM) methods cannot handle free QM solvent molecules during molecular dynamics (MD) simulation because of the diffusion problem.

Size-Consistent Multipartitioning QM/MM: A Stable and Efficient Adaptive QM/MM Method.

We propose a new adaptive QM/MM method, the size-consistent multipartitioning (SCMP) QM/MM scheme, which enables stable and computationally efficient QM/MM simulations. A number of partitionings with identical size of the QM and the MM regions are considered with a new adaptive scheme in order to (1) realize smooth QM/MM switching, (2) introduce a conserved quantity (total energy, Hamiltonian), (3) avoid spurious artificial forces on the QM/MM border, and (4) allow for an efficient parallel implementation. Benchmark simulations performed for "QM water in MM water" show that energy conservation can be significantly improved and the computational efficiency allows treating also larger QM regions, for which previous methods had to face an intractable increase in computer time.

QM/MM simulations of vibrational spectra of bacteriorhodopsin and channelrhodopsin-2.

Channelrhodopsin-2 is a light-gated ion channel, which has been studied intensively over the last decade. Vibrational spectroscopic experiments started to shed light on the structural changes, that occur during the photocycle, especially in the hydrogen-bonded network surrounding the protonated D156 and C128 - the DC gate. However, the interpretation of these experiments was only based on homology models.

Towards an understanding of channelrhodopsin function: simulations lead to novel insights of the channel mechanism.

Channelrhodopsins (ChRs) are light-gated cation channels that mediate ion transport across membranes in microalgae (vectorial catalysis). ChRs gain increasing attention as useful tools for the analysis of neural networks in tissues and living animals (optogenetics). In fact, various mutagenesis approaches have realized practical applications with high reliability by enhancement of the expression level, channel kinetics control, and color tuning.

Structural model of channelrhodopsin.

Channelrhodopsins (ChRs) are light-gated cation channels that mediate ion transport across membranes in microalgae (vectorial catalysis). ChRs are now widely used for the analysis of neural networks in tissues and living animals with light (optogenetics). For elucidation of functional mechanisms at the atomic level, as well as for further engineering and application, a detailed structure is urgently needed.

Color tuning in binding pocket models of the chlamydomonas-type channelrhodopsins.

We examined the shift of absorption maxima between the chlamydomonas-type channelrhodopsins (ChRs) and bacteriorhodopsin (BR). Starting from the BR X-ray structure, we modeled the color tuning in the binding pockets of the ChRs by mutating up to 28 amino acids in the vicinity of the chromophore. By applying the efficient self-consistent charge density functional tight binding (SCC-DFTB) method in a quantum mechanical/molecular mechanical (QM/MM) framework, including explicit polarization and calculating excitation energies with the semiempirical OM2/MRCI method and the ab initio SORCI method, we have shown that multiple mutations in the binding pocket of BR causes large hypsochromic shifts that are of the same order as the experimentally observed shifts of the absorption maxima between BR and the ChRs.

Molecular mechanism of long-range synergetic color tuning between multiple amino acid residues in conger rhodopsin.

The synergetic effects of multiple rhodopsin mutations on color tuning need to be completely elucidated. Systematic genetic studies and spectroscopy have demonstrated an interesting example of synergetic color tuning between two amino acid residues in conger rhodopsin's ancestral pigment (p501): -a double mutation at one nearby and one distant residue led to a significant λ(max) blue shift of 13 nm, whereas neither of the single mutations at these two sites led to meaningful shifts.To analyze the molecular mechanisms of this synergetic color tuning, we performed homology modeling, molecular simulations, and electronic state calculations.

Theoretical modeling of the O-intermediate structure of bacteriorhodopsin.

Bacteriorhodopsin is a prototype of efficient molecular machinery functioning as a light-activated proton pump. Among the five distinct intermediates (K, L, M, N, and O) of the photocycle, there is less structural information on the later stages compared with the early intermediates. Here, we report the structural modeling of the O-intermediate for which the determination of experimental structure remains difficult.