SARS-COV-2 spike protein fragment eases amyloidogenesis of α-synuclein.

Parkinson's disease is accompanied by the presence of amyloids in the brain that are formed of α-synuclein chains. The correlation between COVID-19 and the onset of Parkinson's disease led to the idea that amyloidogenic segments in SARS-COV-2 proteins can induce aggregation of α-synuclein. Using molecular dynamic simulations, we show that the fragment FKNIDGYFKI of the spike protein, which is unique for SARS-COV-2, preferentially shifts the ensemble of α-synuclein monomer toward rod-like fibril seeding conformations and, at the same time, differentially stabilizes this polymorph over the competing twister-like structure. Our results are compared with earlier work relying on a different protein fragment that is not specific for SARS-COV-2.

SARS-COV-2 Spike Protein Fragment eases Amyloidogenesis of α-Synuclein.

Parkinson's Disease is accompanied by presence of amyloids in the brain formed of α-synuclein chains. Correlation between COVID-19 and the onset of Parkinson's disease let to the idea that amyloidogenic segments in SARS-COV-2 proteins can induce aggregation of α-synuclein. Using molecular dynamic simulations, we show that the fragment FKNIDGYFKI of the spike protein, which is unique for SARS-COV-2, shifts preferentially the ensemble of α-synuclein monomer towards rod-like fibril seeding conformations, and at the same time stabilizes differentially this polymorph over the competing twister-like structure. Our results are compared with earlier work relying on a different protein fragment that is not specific for SARS-COV-2.

Human Amylin in the Presence of SARS-COV-2 Protein Fragments.

COVID-19 can lead to the onset of type-II diabetes, which is associated with the aggregation of islet amyloid polypeptides, also called amylin. Using molecular dynamics simulations, we investigate how the equilibrium between amylin monomers in its functional form and fibrils associated with diabetes is altered in the presence of SARS-COV-2 protein fragments. For this purpose, we study the interaction between the fragment SFYVYSRVK of the envelope protein or the fragment FKNIDGYFKI of the spike protein with the monomer and two amylin fibril models. Our results are compared with earlier work studying such interactions for the two different proteins.

Human Amylin in the Presence of SARS-COV-2 Protein Fragments.

Covid-19 can lead to the onset of type-II diabetes which is associated with aggregation of islet amyloid polypeptides, also called amylin. Using molecular dynamics simulations, we investigate how the equilibrium, between amylin monomers in its functional form and fibrils associated with diabetes, is altered in presence of SARS-COV-2 protein fragments. For this purpose, we study the interaction between the fragment SFYVYSRVK of the Envelope protein or the fragment FKNIDGYFKI of the Spike protein with the monomer and two amylin fibril models. Our results are compared with earlier work studying such interactions for two different proteins.

Electronic Spectra of C60 Films Using Screened Range Separated Hybrid Functionals.

We study computationally the electronic spectra of C60 thin films using the recently developed density functional theory (DFT) framework combining a screened range separated hybrid (SRSH) functional with a polarizable continuum model (PCM). The SRSH-PCM approach achieves excellent correspondence between the frontier orbital's energy levels and the ionization potential and electron affinity of the molecular system at the condensed phase and consequently leads to high quality electronic excitation energies when used in time-dependent DFT calculations. Our calculated excited states reproduce the experimentally main reported spectral peaks at the 3.6-4.6 eV energy range and when addressing excitonic effects also reproduce the red-shifted spectral feature. Notably, we analyze the low-lying peak at 2.7 eV and associate it to an excitonic state.

Photoinduced charge transfer in Zn(II) and Au(III)-ligated symmetric and asymmetric bacteriochlorin dyads: A computational study.

The excited-state properties and photoinduced charge-transfer (CT) kinetics in a series of symmetrical and asymmetrical Zn- and Au-ligated meso-meso-connected bacteriochlorin (BChl) complexes are studied computationally. BChl derivatives, which are excellent near-IR absorbing chromophores, are found to play a central role in bacterial photosynthetic reaction centers but are rarely used in artificial solar energy harvesting systems. The optical properties of chemically linked BChl complexes can be tuned by varying the linking group and involving different ligated metal ions. We investigate charge transfer in BChl dyads that are either directly linked or through a phenylene ring (1,4-phenylene) and which are ligating Zn or Au ions. The directly linked dyads with a nearly perpendicular arrangement of the BChl units bear markedly different properties than phenylene linked dyads. In addition, we find that the dielectric dependence of the intramolecular CT rate is very strong in neutral Zn-ligated dyads, whereas cationic Au-ligated dyads show negligible dielectric dependence of the CT rate. Rate constants of the photo induced CT process are calculated at the semiclassical Marcus level and are compared to fully quantum mechanical Fermi's golden rule based values. The rates are calculated using a screened range separated hybrid functional that offers a consistent framework for addressing environment polarization. We study solvated systems in two solvents of a low and a high scalar dielectric constant.

On the Interplay between Electronic Structure and Polarizable Force Fields When Calculating Solution-Phase Charge-Transfer Rates.

We present a comprehensive analysis of the interplay between the choice of an electronic structure method and the effect of using polarizable force fields vs. nonpolarizable force fields when calculating solution-phase charge-transfer (CT) rates. The analysis is based on an integrative approach that combines inputs from electronic structure calculations and molecular dynamics simulations and is performed in the context of the carotenoid-porphyrin-C60 molecular triad dissolved in an explicit tetrahydrofuran (THF) liquid solvent. Marcus theory rate constants are calculated for the multiple CT processes that occur in this system based on either polarizable or nonpolarizable force fields, parameterized using density functional theory (DFT) with either the B3LYP or the Baer-Neuhauser-Livshits (BNL) density functionals. We find that the effect of switching from nonpolarizable to polarizable force fields on the CT rates is strongly dependent on the choice of the density functional. More specifically, the rate constants obtained using polarizable and nonpolarizable force fields differ significantly when B3LYP is used, while much smaller changes are observed when BNL is used. It is shown that this behavior can be traced back to the tendency of B3LYP to overstabilize CT states, thereby pushing the underlying electronic transitions to the deep inverted region, where even small changes in the force fields can lead to significant changes in the CT rate constants. Our results demonstrate the importance of combining polarizable force fields with an electronic structure method that can accurately capture the energies of excited CT states when calculating charge-transfer rates.

Screened Range-Separated Hybrid Functional with Polarizable Continuum Model Overcomes Challenges in Describing Triplet Excitations in the Condensed Phase Using TDDFT.

Long range-corrected (LRC) or range-separated hybrid (RSH) functionals where the long-range (LR) limit of electronic interactions is set to the exact exchange have been shown to correct the tendency of traditional density functional theory (DFT) to underestimate the frontier orbital gap. Consequently, the use of such functionals in calculating electronic excited states using linear response based time-dependent DFT (TDDFT) has been successful in correcting the tendency for underestimating the energies of charge transfer states by DFT-based calculations. More recently formulations of functionals that attenuate the LR limit to address condensed-phase effects to polarize the electronic density have been reported. In particular screened RSH (SRSH) combined with polarizable continuum model (PCM) was benchmarked successfully in reproducing the fundamental gap and charge transfer state energies of molecular systems in the condensed phase. Here we use SRSH-PCM to address triplet excited states, and show its success in obtaining correspondence of the low-lying triplet states to the singlet-triplet gap in a similar way that the fundamental orbital gap corresponds to electron removal and addition energies. Importantly, the accuracy of the SRSH-PCM in calculating triplet excitations stands on the polarization consistent framework in addressing the scalar dielectric constant and without affecting the optimal tuning by triplet energies. The prospect of even further improving the SRSH-PCM accuracy in calculating triplet states can be achieved by optimal tuning on the basis of the spin multiplicity gap.

Excitonic Interactions in Bacteriochlorin Homo-Dyads Enable Charge Transfer: A New Approach to the Artificial Photosynthetic Special Pair.

Excitonically coupled bacteriochlorin (BC) dimers constitute a primary electron donor (special pair) in bacterial photosynthesis and absorbing units in light-harvesting antenna. However, the exact nature of the excited state of these dyads is still not fully understood. Here, we report a detailed spectroscopic and computational investigation of a series of symmetrical bacteriochlorin dimers, where the bacteriochlorins are connected either directly or by a phenylene bridge of variable length. The excited state of these dyads is quenched in high-dielectric solvents, which we attribute to photoinduced charge transfer. The mixing of charge transfer with the excitonic state causes accelerated (within 41 ps) decay of the excited state for the directly linked dyad, which is reduced by orders of magnitude with each additional phenyl ring separating the bacteriochlorins. These results highlight the origins of the excited-state dynamics in symmetric BC dyads and provide a new model for studying the primary processes in photosynthesis and for the development of artificial, biomimetic systems for solar energy conversion.

Enhancing charge mobilities in organic semiconductors by selective fluorination: a design approach based on a quantum mechanical perspective.

Selective fluorination of organic semiconducting molecules is proposed as a means to achieving enhanced hole mobility. Naphthalene is examined here as a root molecular system with fluorination performed at various sites. Our quantum chemical calculations show that selective fluorination can enhance attractive intermolecular interactions while reducing charge trapping. Those observations suggest a design principle whereby fluorination is utilized for achieving high charge mobilities in the crystalline form. The utility of this design principle is demonstrated through an application to perylene, which is an important building block of organic semiconducting materials. We also show that a quantum mechanical perspective of nuclear degrees of freedom is crucial for a reliable description of charge transport.

Photoinduced Homolytic Bond Cleavage of the Central Si-C Bond in Porphyrin Macrocycles Is a Charge Polarization Driven Process.

Photoinduced cleavage of the bond between the central Si atom in porphyrin macrocycles and the neighboring carbon atom of an axial alkyl ligand is investigated by both experimental and computational tools. Photolysis and electron paramagnetic resonance measurements indicate that the Si-C bond cleavage of Si-phthalocyanine occurs through a homolytic process. The homolytic process follows a low-lying electronic excitation of about 1.8 eV that destabilizes the carbide bond of similar bond dissociation energy. Using electronic structure calculations, we provide insight into the nature of the excited state and the resulting photocleavage mechanism. We explain this process by finding that the electronic excited state is of a charge transfer character from the axial ligand toward the macrocycle in the reverse direction of the ground state polarization. We find that the homolytic process yielding the radical intermediate is energetically the most stable mechanistic route. Furthermore, we demonstrate using our computational approach that changing the phthalocyanine to smaller ring system enhances the homolytic photocleavage of the Si-C bond by reducing the energetic barrier in the relevant excited states.

Probing DNA clamps with single-molecule force spectroscopy.

Detailed mechanisms of DNA clamps in prokaryotic and eukaryotic systems were investigated by probing their mechanics with single-molecule force spectroscopy. Specifically, the mechanical forces required for the Escherichia coli and Saccharomyces cerevisiae clamp opening were measured at the single-molecule level by optical tweezers. Steered molecular dynamics simulations further examined the forces involved in DNA clamp opening from the perspective of the interface binding energies associated with the clamp opening processes. In combination with additional molecular dynamics simulations, we identified the contact networks between the clamp subunits that contribute significantly to the interface stability of the S.cerevisiae and E. coli clamps. These studies provide a vivid picture of the mechanics and energy landscape of clamp opening and reveal how the prokaryotic and eukaryotic clamps function through different mechanisms.

Conserved structural chemistry for incision activity in structurally non-homologous apurinic/apyrimidinic endonuclease APE1 and endonuclease IV DNA repair enzymes.

Non-coding apurinic/apyrimidinic (AP) sites in DNA form spontaneously and as DNA base excision repair intermediates are the most common toxic and mutagenic in vivo DNA lesion. For repair, AP sites must be processed by 5' AP endonucleases in initial stages of base repair. Human APE1 and bacterial Nfo represent the two conserved 5' AP endonuclease families in the biosphere; they both recognize AP sites and incise the phosphodiester backbone 5' to the lesion, yet they lack similar structures and metal ion requirements. Here, we determined and analyzed crystal structures of a 2.4 Å resolution APE1-DNA product complex with Mg(2+) and a 0.92 Å Nfo with three metal ions. Structural and biochemical comparisons of these two evolutionarily distinct enzymes characterize key APE1 catalytic residues that are potentially functionally similar to Nfo active site components, as further tested and supported by computational analyses. We observe a magnesium-water cluster in the APE1 active site, with only Glu-96 forming the direct protein coordination to the Mg(2+). Despite differences in structure and metal requirements of APE1 and Nfo, comparison of their active site structures surprisingly reveals strong geometric conservation of the catalytic reaction, with APE1 catalytic side chains positioned analogously to Nfo metal positions, suggesting surprising functional equivalence between Nfo metal ions and APE1 residues. The finding that APE1 residues are positioned to substitute for Nfo metal ions is supported by the impact of mutations on activity. Collectively, the results illuminate the activities of residues, metal ions, and active site features for abasic site endonucleases.

Specific and nonspecific effects of glycosylation.

Glycosylation regulates vital cellular processes and dramatically influences protein folding and stability. In particular, experiments have demonstrated that asparagine (N)-linked disaccharides drive a "conformational switch" in a model peptide. The present work investigates this conformational switch via extensive atomically detailed replica exchange molecular dynamics simulations in explicit solvent. To distinguish the effects of specific and nonspecific interactions upon the peptide conformational ensemble, these simulations considered model peptides that were N-linked to a disaccharide and to a steric crowder of the same shape. The simulations are remarkably consistent with experiment and provide detailed insight into the peptide structure ensemble. They suggest that steric crowding by N-linked disaccharides excludes extended conformations, but does not significantly impact the tetrahedral structure of the surrounding solvent or otherwise alter the peptide free energy surface. However, the combination of steric crowding with specific hydrogen bonds and hydrophobic stacking interactions more dramatically impacts the peptide ensemble and stabilizes new structures.

Dynamics of H+ + CO at E(Lab) = 30 eV.

The astrophysically relevant system H(+) + CO (v(i) = 0) → H(+) + CO (v(f)) at E(Lab) = 30 eV is studied with the simplest-level electron nuclear dynamics (SLEND) method. This investigation follows previous successful SLEND studies of H(+) + H(2) and H(+) + N(2) at E(Lab) = 30 eV [J. Morales, A. Diz, E. Deumens, and Y. Öhrn, J. Chem. Phys. 103(23), 9968 (1995); C. Stopera, B. Maiti, T. V. Grimes, P. M. McLaurin, and J. A. Morales, J. Chem. Phys. 134(22), 224308 (2011)]. SLEND is a direct, time-dependent, variational, and non-adiabatic method that adopts a classical-mechanics description for the nuclei and a single-determinantal wavefunction for the electrons. A canonical coherent-states (CS) procedure associated with SLEND reconstructs quantum vibrational properties from the SLEND classical dynamics. Present SLEND results include reactivity predictions, snapshots of the electron density evolution, average vibrational energy transfers, rainbow angle predictions, total and vibrationally resolved differential cross sections (DCS), and average vibrational excitation probabilities. SLEND results are compared with available data from experiments and vibrational close-coupling rotational infinite-order sudden (VCC-RIOS) approximation calculations. Present simulations employ four basis sets: STO-3G, 6-31G, 6-31G**, and cc-pVDZ to determine their effect on the results. SLEND simulations predict non-charge-transfer scattering and CO collision-induced dissociation as the main reactions. SLEND/6-31G, /6-31G**, and /cc-pVDZ predict rainbow angles and total DCS in excellent agreement with experiments and more accurate than their VCC-RIOS counterparts. SLEND/6-31G** and /cc-pVDZ predict vibrationally resolved DCS for v(f) = 0-2 in satisfactory experimental agreement, but less accurate than their comparable H(+) + CO VCC-RIOS and H(+) + H(2) and H(+) + N(2) SLEND results. SLEND∕6-31G** and ∕cc-pVDZ predict qualitatively correct average vibrational excitation probabilities, which are quantitatively correct for v(f) = 2, but under(over)estimated for v(f) = 0(1). Discrepancies in some H(+) + CO SLEND vibrational properties, not observed in H(+) + H(2) and H(+) + N(2) SLEND results, are attributed to the moderately overestimated SLEND vibrational energy through its effect upon the canonical CS probabilities. Correction of that energy to its experimental values produces a remarkable improvement in the average vibrational excitation probabilities. Ways to obtain more accurate vibrational properties with higher-level versions of electron nuclear dynamics are discussed.

Dynamics of H+ + N2 at E(Lab) = 30 eV.

The H(+) + N(2) system at E(Lab) = 30 eV, relevant in astrophysics, is investigated with the simplest-level electron nuclear dynamics (SLEND) method. SLEND is a time-dependent, direct, variational, non-adiabatic method that employs a classical-mechanics description for the nuclei and a single-determinantal wavefunction for the electrons. A canonical coherent-states procedure, intrinsic to SLEND, is used to reconstruct quantum vibrational properties from the SLEND classical mechanics. Present simulations employ three basis sets: STO-3G, 6-31G, and 6-31G∗∗, to determine their effect on the results, which include reaction visualizations, product predictions, and scattering properties. Present simulations predict non-charge-transfer scattering and N(2) collision-induced dissociation as the main reactions. Average vibrational energy transfer, H(+) energy-loss spectra, rainbow angle, and elastic vibrational differential cross sections at the SLEND∕6-31G∗∗ level agree well with available experimental data. SLEND∕6-31G∗∗ results are comparable to those calculated with the vibrational close-coupling rotational infinite-order sudden approximation and the quasi-classical trajectory method.

HSAB principle applied to the time evolution of chemical reactions.

Time evolution of various reactivity parameters such as electronegativity, hardness, and polarizability associated with a collision process between a proton and an X- atom/ion (X = He, Li(+), Be(2+), B(3+), C(4+)) in its ground ((1)S) and excited((1)P,(1)D,(1)F) electronic states as well as various complexions of a two-state ensemble is studied using time-dependent and excited-state density functional theory. This collision process may be considered to be a model mimicking the actual chemical reaction between an X-atom/ion and a proton to give rise to an XH(+) molecule. A favorable dynamical process is characterized by maximum hardness and minimum polarizability values according to the dynamical variants of the principles of maximum hardness and minimum polarizability. An electronic excitation or an increase in the excited-state contribution in a two-state ensemble makes the system softer and more polarizable, and the proton, being a hard acid, gradually prefers less to interact with X as has been discerned through the drop in maximum hardness value and the increase in the minimum polarizability value when the actual chemical process occurs. Among the noble gas elements, Xe is the most reactive. During the reaction: H(2) + H(+) --> H(3)(+) hardness maximizes and polarizability minimizes and H(2) is more reactive in its excited state. Regioselectivity of proton attack in the O-site of CO is clearly delineated wherein HOC(+) may eventually rearrange itself to go to the thermodynamically more stable HCO(+).