Chirality-Induced Spin Selectivity: Analysis of Density Functional Theory Calculations.

Chirality-induced spin selectivity (CISS), which was demonstrated in several molecular and material systems, has drawn much interest recently. The phenomenon, described in electron transport by the difference in the transport rate of electrons of opposite spins through a chiral system, is however not fully understood. Herein, we employed density functional theory in conjunction with spin-orbit coupling to evaluate the percent spin-polarization in a device setup with finite electrodes at zero bias, using an electron transport program developed in-house. To study the interface effects and the level of theory considered, we investigated a helical oligopeptide chain, an intrinsically chiral gold cluster, and a helicene model system that was previously studied (Zöllner et al. J. Chem. Theory Comput. 2020, 16, 7357-7371). We find that the magnitude of the spin-polarization depends on the chiral system-electrode interface that is modeled by varying the interface boundary between the system's regions, on the method of calculating spin-orbit coupling, and on the exchange-correlation functional, e.g., the amount of exact exchange in the hybrid functionals. In addition, to assess the effects of bias, we employ the nonequilibrium Green's function formalism in the Quantum Atomistix Toolkit program, showing that the spin-flip terms could be important in calculating the CISS effect. Although understanding CISS in comparison to experiment is still not resolved, our study provides intrinsic responses from first-principles calculations.

Effects of inter-radical interactions and scavenging radicals on magnetosensitivity: spin dynamics simulations of proposed radical pairs.

Although the magnetosensitivity to weak magnetic fields, such as the geomagnetic field, which was exhibited by radical pairs that are potentially responsible for avian navigation, has been previously investigated by spin dynamics simulations, understanding this behavior for proposed radical pairs in other species is limited. These include, for example, radical pairs formed in the single-cell green alga Chlamydomonas reinhardtii (CraCRY) and in Columba livia (ClCRY4). In addition, the radical pair of FADH• with the one-electron reduced cyclobutane thymine dimer that was shown to be sensitive to weak magnetic fields has been of interest. In this work, we investigated the directional magnetosensitivity of these radical pairs to a weak magnetic field by spin dynamics simulations. We find significant reduction in the magnetosensitivity by inclusion of dipolar and exchange interactions, which can be mitigated by a scavenging radical, as demonstrated for the [FAD•- TyrD•] radical pair in CraCRY, but not for the [FADH• T□T•-] radical pair because of the large exchange coupling. The directional magnetosensitivity of the ClCRY4 [FAD•- TyrE•] radical pair can survive this adverse effect even without the scavenging reaction, possibly motivating further experimental exploration.

Electron transfer and spin dynamics of the radical-pair in the cryptochrome from Chlamydomonas reinhardtii by computational analysis.

In an effort to elucidate the origin of avian magnetoreception, it was postulated that a radical-pair formed in a cryptochrome upon light activation provided the basis for the mechanism that enables an inclination compass sensitive to the geomagnetic field. Photoreduction in this case involves formation of a flavin adenine dinucleotide (FAD)-tryptophan (TRP) radical-pair, following electron transfer within a conserved TRP triad in the cryptochrome. Recently, an animal-like cryptochrome from Chlamydomonas reinhardtii (CraCRY) was analyzed, demonstrating the role of a fourth aromatic residue, which serves as a terminal electron donor in the photoreduction pathway, resulting in the creation of a more distal radical-pair and exhibiting fast electron transfer. In this work, we investigated the electron transfer in CraCRY with a combination of free energy molecular dynamics (MD) simulations, frozen density functional theory, and QM/MM MD simulations, supporting the suggestion of a proton coupled electron transfer mechanism. Spin dynamics simulations discerned details on the dependence of the singlet yield on the direction of the external magnetic field for the [FAD•- TYRH•+] and [FAD•- TYR•] radical-pairs in CraCRY, in comparison with the previously modeled [FAD•- TRPH•+] radical-pair.

Coupling Drosophila melanogaster Cryptochrome Light Activation and Oxidation of the Kvß Subunit Hyperkinetic NADPH Cofactor.

Motivated by the observations on the involvement of light-induced processes in the Drosophila melanogaster cryptochrome (DmCry) in regulation of the neuronal firing rate, which is achieved by a redox-state change of its voltage-dependent K+ channel Kvß subunit hyperkinetic (Hk) reduced nicotinamide adenine dinucleotide phosphate (NADPH) cofactor, we propose in this work two hypothetical pathways that may potentially enable such coupling. In the first pathway, triggered by blue-light-induced formation of a radical pair [FAD•-TRP•+] in DmCry, the hole (TRP•+) may hop to Hk, for example, through a tryptophan chain and oxidize NADPH, possibly leading to inhibition of the N-terminus inactivation in the K+ channel. In a second possible pathway, DmCry's FAD•- is reoxidized by molecular oxygen, producing H2O2, which then diffuses to Hk and oxidizes NADPH. In this work, by applying a combination of quantum and empirical-based methods for free-energy calculations, we find that the oxidation of NADPH by TRP•+ or H2O2 and the reoxidation of FAD•- by O2 are thermodynamically feasible. Our results may have an implication in identifying a magnetic sensing signal transduction pathway, specifically upon Drosophila's Hk NADPH cofactor oxidation, with a subsequent inhibition of the K+ channel N-terminus inactivation gate, permitting K+ flux.

Bound Flavin-Cytochrome Model of Extracellular Electron Transfer in Shewanella oneidensis: Analysis by Free Energy Molecular Dynamics Simulations.

Flavins are known to enhance extracellular electron transfer (EET) in Shewanella oneidensis MR-1 bacteria, which reduce electron acceptors through outer-membrane (OM) cytochromes c. Free-shuttle and bound-redox cofactor mechanisms were proposed to explain this enhancement, but recent electrochemical reports favor a flavin-bound model, proposing two one-electron reductions of flavin, namely, oxidized (Ox) to semiquinone (Sq) and semiquinone to hydroquinone (Hq), at anodic and cathodic conditions, respectively. In this work, to provide a mechanistic understanding of riboflavin (RF) binding at the multiheme OM cytochrome OmcA, we explored binding configurations at hemes 2, 5, 7, and 10. Subsequently, on the basis of molecular dynamics (MD) simulations, binding free energies and redox potential shifts upon RF binding for the Ox/Sq and Sq/Hq reductions were analyzed. Our results demonstrated an upshift in the Ox/Sq and a downshift in the Sq/Hq redox potentials, consistent with a bound RF-OmcA model. Furthermore, binding free energy MD simulations indicated an RF binding preference at heme 7. MD simulations of the OmcA-MtrC complex interfacing at hemes 5 revealed a small interprotein redox potential difference with an electron transfer rate of 10(7)-10(8)/s.

Photoactivation of cryptochromes from Drosophila melanogaster and Sylvia borin: insight into the chemical compass mechanism by computational investigation.

Although behavioral studies demonstrated light-induced magnetoreception in the insect Drosophila melanogaster, gaining insight into the possibility that a radical-pair mechanism accounts for the magnetic response of the cryptochrome (DmCry1) is complicated by a number of factors. In addition, the mechanism of magnetoreception for the cryptochrome from the garden warbler bird Sylvia borin (gwCry1a), which demonstrated a long-lived radical pair by transient optical absorption measurements, has also not been rationalized. To assess potential feasibility of a radical-pair mechanism in DmCry1 and gwCry1a, formed by excitation and electron transfer between a Trp-triad and flavin adenine dinucleotide (FAD), further separated by electron transfer within the triad, we applied a combination of theoretical methods, including homology modeling and molecular dynamics (MD) for structure refinement, high-level ab initio theory, and MD simulations using a polarizable force-field for prediction of pKa and the electron transfer rate. Calculated excitation energies, followed by electron transfer in model compounds of DmCry1 that assume proton transfer in conjunction with electron transfer from Trp (W420) to FAD and the predicted pKa for the proximate residue to FAD (Cys416), support a radical-pair mechanism. Furthermore, free-energy and reorganization energies for the Trp-triad in DmCry1 demonstrate facile electron transfer, explained by the local protein environment and exposure to solvent, which in turn enables a large enough distance separation for the radical-pair partners. Results for gwCry1a demonstrated the importance of accounting for relaxed excited-state geometries in validating the first stage of a radical-pair mechanism. This work provides insight into the so-called chemical compass mechanism to explain magnetic-field sensing in DmCry1 and gwCry1a, expanding on previous work on the cyrptochrome from the plant Arabidopsis thaliana (Solov'yov et al. J. Am. Chem. Soc. 2012, 134, 18046-18052. Solov'yov et al., Sci. Rep. 2014, 4, 1-8.).

Electronic properties of a graphene device with peptide adsorption: insight from simulation.

In this work, to explain doping behavior of single-layer graphene upon HSSYWYAFNNKT (P1) and HSSAAAAFNNKT (P1-3A) adsorption in field-effect transistors (GFETs), we applied a combined computational approach, whereby peptide adsorption was modeled by molecular dynamics simulations, and the lowest energy configuration was confirmed by density functional theory calculations. On the basis of the resulting structures of the hybrid materials, electronic structure and transport calculations were investigated. We demonstrate that π-π stacking of the aromatic residues and proximate peptide backbone to the graphene surface in P1 have a role in the p-doping. These results are consistent with our experimental observation of the GFET's p-doping even after a 24-h annealing procedure. Upon substitution of three of the aromatic residues to Ala in (P1-3A), a considerable decrease from p-doping is observed experimentally, demonstrating n-doping as compared to the nonadsorbed device, yet not explained based on the atomistic MD simulation structures. To gain a qualitative understanding of P1-3A's adsorption over a longer simulation time, which may differ from aromatic amino acid residues' swift anchoring on the surface, we analyzed equilibrated coarse-grain simulations performed for 500 ns. Desorption of the Ala residues from the surface was shown computationally, which could in turn affect charge transfer, yet a full explanation of the mechanism of n-doping will require elucidation of differences between various aromatic residues as dependent on peptide composition, and inclusion of effects of the substrate and environment, to be considered in future work.

Inhibition of biocatalysis in [Fe-Fe] hydrogenase by oxygen: molecular dynamics and density functional theory calculations.

Designing O(2)-tolerant hydrogenases is a major challenge in applying [Fe-Fe]H(2)ases for H(2) production. The inhibition involves transport of oxygen through the enzyme to the H-cluster, followed by binding and subsequent deactivation of the active site. To explore the nature of the oxygen diffusion channel for the hydrogenases from Desulfovibrio desulfuricans (Dd) and Clostridium pasteurianum (Cp), empirical molecular dynamics simulations were performed. The dynamic nature of the oxygen pathways in Dd and Cp was elucidated, and insight is provided, in part, into the experimental observation on the difference of oxygen inhibition in Dd and the hydrogenase from Clostridium acetobutylicum (Ca, assumed homologous to Cp). Further, to gain an understanding of the mechanism of oxygen inhibition of the [Fe-Fe]H(2)ase, density functional theory calculations of model compounds composed of the H-cluster and proximate amino acids are reported. Confirmation of the experimentally based suppositions on inactivation by oxygen at the [2Fe](H) domain is provided, validating the model compounds used and oxidation state assumptions, further explaining the mode of damage. This unified approach provides insight into oxygen diffusion in the enzyme, followed by deactivation at the H-cluster.

Design parameters for tuning the type 1 Cu multicopper oxidase redox potential: insight from a combination of first principles and empirical molecular dynamics simulations.

The redox potentials and reorganization energies of the type 1 (T1) Cu site in four multicopper oxidases were calculated by combining first principles density functional theory (QM) and QM/MM molecular dynamics (MD) simulations. The model enzymes selected included the laccase from Trametes versicolor, the laccase-like enzyme isolated from Bacillus subtilis, CueO required for copper homeostasis in Escherichia coli, and the small laccase (SLAC) from Streptomyces coelicolor. The results demonstrated good agreement with experimental data and provided insight into the parameters that influence the T1 redox potential. Effects of the immediate T1 Cu site environment, including the His(N(δ))-Cys(S)-His(N(δ)) and the axial coordinating amino acid, as well as the proximate H(N)(backbone)-S(Cys) hydrogen bond, were discerned. Furthermore, effects of the protein backbone and side-chains, as well as of the aqueous solvent, were studied by QM/MM molecular dynamics (MD) simulations, providing an understanding of influences beyond the T1 Cu coordination sphere. Suggestions were made regarding an increase of the T1 redox potential in SLAC, i.e., of Met198 and Thr232 in addition to the axial amino acid Met298. Finally, the results of this work presented a framework for understanding parameters that influence the Type 1 Cu MCO redox potential, useful for an ever-growing range of laccase-based applications.

Biophysical properties of membrane-active peptides based on micelle modeling: a case study of cell-penetrating and antimicrobial peptides.

We investigated the molecular mechanisms of short peptides interacting with membrane-mimetic systems. Three short peptides were selected for this study: penetratin as a cell-penetrating peptide (CPP), and temporin A and KSL as antimicrobial peptides (AMP). We investigated the detailed interactions of the peptides with dodecylphosphocholine (DPC) and sodium dodecyl sulfate (SDS) micelles, and the subsequent peptide insertion based on free energy calculations by using all-atomistic molecular dynamics simulations with the united atom force field and explicit solvent models. First, we found that the free energy barrier to insertion for the three peptides is dependent on the chemical composition of the micelles. Because of the favorable electrostatic interactions between the peptides and the headgroups of lipids, the insertion barrier into an SDS micelle is less than a DPC micelle. Second, the peptides' secondary structures may play a key role in their binding and insertion ability, particularly for amphiphilic peptides such as penetratin and KSL. The secondary structures with a stronger ability to bind with and insert into micelles are the ones that account for a smaller surface area of hydrophobic core, thus offering a possible criterion for peptide design with specific functionalities.

Toward understanding amino acid adsorption at metallic interfaces: a density functional theory study.

In examining adsorption of a few selected single amino acids on Au and Pd cluster models by density functional theory calculations, we have shown that specific side-chain binding affinity to the surface may occur because of a combination of effects, including charge transfer. Larger binding was calculated at the Pd interface. In addition, the interplay between amino acid solvation and adsorption at the interface was considered from first principles. This analysis serves as the first step toward gaining a more accurate understanding of specific interactions at the interface of biological-metal nanostructures than has been attempted in the past.

Using the constrained DFT approach in generating diabatic surfaces and off diagonal empirical valence bond terms for modeling reactions in condensed phases.

The empirical valence bond (EVB) model provides an extremely powerful way for modeling and analyzing chemical reactions in solutions and proteins. However, this model is based on the unverified assumption that the off diagonal elements of the EVB Hamiltonian do not change significantly upon transfer of the reacting system from one phase to another. This ad hoc assumption has been rationalized by its consistency with empirically observed linear free energy relationships, as well as by other qualitative considerations. Nevertheless, this assumption has not been rigorously established. The present work explores the validity of the above EVB key assumption by a rigorous numerical approach. This is done by exploiting the ability of the frozen density functional theory (FDFT) and the constrained density functional theory (CDFT) models to generate convenient diabatic states for QM/MM treatments, and thus to examine the relationship between the diabatic and adiabatic surfaces, as well as the corresponding effective off diagonal elements. It is found that, at least for the test case of S(N)()2 reactions, the off diagonal element does not change significantly upon moving from the gas phase to solutions and thus the EVB assumption is valid and extremely useful.

Frozen density functional free energy simulations of redox proteins: computational studies of the reduction potential of plastocyanin and rusticyanin.

The evaluation of reduction potentials of proteins by ab initio approaches presents a major challenge for computational chemistry. This is addressed in the present investigation by reporting detailed calculations of the reduction potentials of the blue copper proteins plastocyanin and rusticyanin using the QM/MM all-atom frozen density functional theory, FDFT, method. The relevant ab initio free energies are evaluated by using a classical reference potential. This approach appears to provide a general consistent and effective way for reproducing the configurational ensemble needed for consistent ab initio free energy calculations. The FDFT formulation allows us to treat a large part of the protein quantum mechanically by a consistently coupled QM/QM/MM embedding method while still retaining a proper configurational sampling. To establish the importance of proper configurational sampling and the need for a complete representation of the protein+solvent environment, we also consider several classical approaches. These include the semi-macroscopic PDLD/S-LRA method and classical all-atom simulations with and without a polarizable force field. The difference between the reduction potentials of the two blue copper proteins is reproduced in a reasonable way, and its origin is deduced from the different calculations. It is found that the protein permanent dipole tunes down the reduction potential for plastocyanin compared to the active site in regular water solvent, whereas in rusticyanin it is instead tuned up. This electrostatic environment, which is the major effect determining the reduction potential, is a property of the entire protein and solvent system and cannot be ascribed to any particular single interaction.