Reduction of the virtual space for coupled-cluster excitation energies of large molecules and embedded systems

Peer reviewe

To catalyze or not to catalyze: elucidation of the subtle differences between the hexameric capsules of pyrogallolarene and resorcinarene

The closely related, self-assembled resorcinarene and pyrogallolarene capsules display contrasting and puzzling encapsulation behaviors. Herein, we elucidate the reasons for these differences by combining experimental studies and DFT calculations. Furthermore, we report that, in contrast to the resorcinarene capsule, the pyrogallolarene derivative is not capable of catalyzing reactions with cationic transition states. The molecular mechanisms responsible for these observations are probed in detail

Benchmarking the performance of time-dependent density functional theory methods on biochromophores

Quantum chemical calculations are important for elucidating light-capturing mechanisms in photobiological systems. The time-dependent density functional theory (TDDFT) has become a popular methodology because of its balance between accuracy and computational scaling, despite its problems in describing, for example, charge transfer states. As a step toward systematically understanding the performance of TDDFT calculations on biomolecular systems, we study here 17 commonly used density functionals, including seven long-range separated functionals, and compare the obtained results with excitation energies calculated at the approximate second order coupled-cluster theory level (CC2). The benchmarking set includes the first five singlet excited states of 11 chemical analogues of biochromophores from the green fluorescent protein, rhodopsin/bacteriorhodopsin (Rh/bR), and the photoactive yellow protein. We find that commonly used pure density functionals such as BP86, PBE, M11-L, and hybrid functionals with 20-25% of Hartree-Fock (HF) exchange (B3LYP, PBE0) have a tendency to consistently underestimate vertical excitation energies (VEEs) relative to the CC2 values, whereas hybrid density functionals with around 50% HF exchange such as BHLYP, PBE50, and M06-2X and long-range corrected functionals such as CAM-B3LYP, omega PBE, omega PBEh, omega B97X, omega B97XD, BNL, and M11 overestimate the VEEs. We observe that calculations using the CAM-B3LYP and omega PBEh functionals with 65% and 100% long-range HF exchange, respectively, lead to an overestimation of the VEEs by 0.2-0.3 eV for the benchmarking set. To reduce the systematic error, we introduce here two new empirical functionals, CAMh-B3LYP and omega hPBE0, for which we adjusted the long-range HF exchange to 50%. The introduced parameterization reduces the mean signed average (MSA) deviation to 0.07 eV and the root mean square (rms) deviation to 0.17 eV as compared to the CC2 values. In the present study, TDDFT calculations using the aug-def2-TZVP basis sets, the best performing functionals relative to CC2 are omega hPBE0 (rms = 0.17, MSA = 0.06 eV); CAMh-B3LYP (rms = 0.16, MSA = 0.07 eV); and PBE0 (rms = 0.23, MSA = 0.14 eV). For the popular range-separated CAM-B3LYP functional, we obtain an rms value of 0.31 eV and an MSA value of 0.25 eV, which can be compared with the rms and MSA values of 0.37 and -0.31 eV, respectively, as obtained at the B3LYP level.Peer reviewe

Absorption shifts of diastereotopically ligated chlorophyll dimers of photosystem I

The light-harvesting chlorophyll (Chl) molecules of photosynthetic systems form the basis for light-driven energy conversion. In biological environments, the Chl chromophores occur in two distinct diastereotopic configurations, where the alpha and beta configurations have a magnesium-ligating histidine residue and a 17-propionic acid moiety on the opposite side or on the same side of the Chl ring, respectively. Although beta-ligated Chl dimers occupy conserved positions around the reaction center of photosystem I (PSI), the functional relevance of the alpha/beta configuration of the ligation is poorly understood. We employ here correlated ab initio calculations using the algebraic-diagrammatic construction through second order (ADC(2)) and the approximate second-order coupled cluster (CC2) methods in combination with the reduced virtual space (RVS) approach in studies of the intrinsic excited-state properties of alpha-ligated and beta-ligated Chl dimers of PSI. Our ab initio calculations suggest that the absorption of the alpha-ligated reaction-center Chl dimer of PSI is redshifted by 0.13-0.14 eV in comparison to the beta-ligated dimers due to combined excitonic coupling and strain effects. We also show that time-dependent density functional theory (TDDFT) calculations using range-separated density functionals underestimate the absorption shift between the alpha- and beta-ligated dimers. Our findings may provide a molecular starting point for understanding the energy flow in natural photosynthetic systems, as well as a blueprint for developing new molecules that convert sunlight into other forms of energy.Peer reviewe

Terminal Electron–Proton Transfer Dynamics in the Quinone Reduction of Respiratory Complex I

Complex I functions as a redox-driven proton pump in aerobic respiratory chains. By reducing quinone (Q), complex I employs the free energy released in the process to thermodynamically drive proton pumping across its membrane domain. The initial Q reduction step plays a central role in activating the proton pumping machinery. In order to probe the energetics, dynamics, and molecular mechanism for the proton-coupled electron transfer process linked to the Q reduction, we employ here multiscale quantum and classical molecular simulations. We identify that both ubiquinone (UQ) and menaquinone (MQ) can form stacking and hydrogen-bonded interactions with the conserved Q binding-site residue His-38 and that conformational changes between these binding modes modulate the Q redox potentials and the rate of electron transfer (eT) from the terminal N2 iron-sulfur center. We further observe that, while the transient formation of semiquinone is not proton-coupled, the second eT process couples semiconcerted proton uptake from conserved tyrosine (Tyr-87) and histidine (His-38) residues within the active site. Our calculations indicate that both UQ and MQ have low redox potentials around -260 and -230 mV, respectively, in the Q-binding site, respectively, suggesting that release of the Q toward the membrane is coupled to an energy transduction step that could thermodynamically drive proton pumping in complex I.Peer reviewe

Energetics and dynamics of a light-driven sodium-pumping rhodopsin

The conversion of light energy into ion gradients across biological membranes is one of the most fundamental reactions in primary biological energy transduction. Recently, the structure of the first light-activated Na+ pump, Krokinobacter eikastus rhodopsin 2 (KR2), was resolved at atomic resolution [Kato HE, et al. (2015) Nature 521: 48-53]. To elucidate its molecular mechanism for Na+ pumping, we perform here extensive classical and quantum molecular dynamics (MD) simulations of transient photocycle states. Our simulations show how the dynamics of key residues regulate water and ion access between the bulk and the buried light-triggered retinal site. We identify putative Na+ binding sites and show how protonation and conformational changes gate the ion through these sites toward the extracellular side. We further show by correlated ab initio quantum chemical calculations that the obtained putative photocycle intermediates are in close agreement with experimental transient optical spectroscopic data. The combined results of the ion translocation and gating mechanisms in KR2 may provide a basis for the rational design of novel light-driven ion pumps with optogenetic applications.Peer reviewe

Molecular Basis of the Electron Bifurcation Mechanism in the [FeFe]-Hydrogenase Complex HydABC

Electron bifurcation is a fundamental energy coupling mechanism widespread in microorganisms that thrive under anoxic conditions. These organisms employ hydrogen to reduce CO2, but the molecular mechanisms have remained enigmatic. The key enzyme responsible for powering these thermodynamically challenging reactions is the electron-bifurcating [FeFe]-hydrogenase HydABC that reduces low-potential ferredoxins (Fd) by oxidizing hydrogen gas (H2). By combining single-particle cryo-electron microscopy (cryoEM) under catalytic turnover conditions with site-directed mutagenesis experiments, functional studies, infrared spectroscopy, and molecular simulations, we show that HydABC from the acetogenic bacteria Acetobacterium woodii and Thermoanaerobacter kivui employ a single flavin mononucleotide (FMN) cofactor to establish electron transfer pathways to the NAD(P)+ and Fd reduction sites by a mechanism that is fundamentally different from classical flavin-based electron bifurcation enzymes. By modulation of the NAD(P)+ binding affinity via reduction of a nearby iron–sulfur cluster, HydABC switches between the exergonic NAD(P)+ reduction and endergonic Fd reduction modes. Our combined findings suggest that the conformational dynamics establish a redox-driven kinetic gate that prevents the backflow of the electrons from the Fd reduction branch toward the FMN site, providing a basis for understanding general mechanistic principles of electron-bifurcating hydrogenases

Redox-coupled quinone dynamics in the respiratory complex I

Complex I couples the free energy released from quinone (Q) reduction to pump protons across the biological membrane in the respiratory chains of mitochondria and many bacteria. The Q reduction site is separated by a large distance from the proton-pumping membrane domain. To address the molecular mechanism of this long-range proton-electron coupling, we perform here full atomistic molecular dynamics simulations, free energy calculations, and continuum electrostatics calculations on complex I from Thermus thermophilus. We show that the dynamics of Q is redox-state-dependent, and that quinol, QH(2), moves out of its reduction site and into a site in the Q tunnel that is occupied by a Q analog in a crystal structure of Yarrowia lipolytica. We also identify a second Q-binding site near the opening of the Q tunnel in the membrane domain, where the Q headgroup forms strong interactions with a cluster of aromatic and charged residues, while the Q tail resides in the lipid membrane. We estimate the effective diffusion coefficient of Q in the tunnel, and in turn the characteristic time for Q to reach the active site and for QH2 to escape to the membrane. Our simulations show that Q moves along the Q tunnel in a redox-state-dependent manner, with distinct binding sites formed by conserved residue clusters. The motion of Q to these binding sites is proposed to be coupled to the proton-pumping machinery in complex I.Peer reviewe

Structure of inhibitor-bound mammalian complex I

Funder: The Swedish National Infrastructure for Computing (SNIC, 2019/2-3) UK National Electron Bio-Imaging Centre (eBIC) at the Diamond Light Source, proposal EM16309, funded by the Wellcome Trust, MRC and BBSRCAbstract: Respiratory complex I (NADH:ubiquinone oxidoreductase) captures the free energy from oxidising NADH and reducing ubiquinone to drive protons across the mitochondrial inner membrane and power oxidative phosphorylation. Recent cryo-EM analyses have produced near-complete models of the mammalian complex, but leave the molecular principles of its long-range energy coupling mechanism open to debate. Here, we describe the 3.0-Å resolution cryo-EM structure of complex I from mouse heart mitochondria with a substrate-like inhibitor, piericidin A, bound in the ubiquinone-binding active site. We combine our structural analyses with both functional and computational studies to demonstrate competitive inhibitor binding poses and provide evidence that two inhibitor molecules bind end-to-end in the long substrate binding channel. Our findings reveal information about the mechanisms of inhibition and substrate reduction that are central for understanding the principles of energy transduction in mammalian complex I