Comparing the influence of explicit and implicit solvation models on site-specific thermodynamic stability of proteins.

Understanding the molecular basis for protein stability requires a thermodynamic analysis of protein folding. Thermodynamic analysis is often performed by sampling many atomistic conformations using molecular simulations that employ either explicit or implicit water models. However, it remains unclear to what extent thermodynamic results from different solvation models are reliable at the molecular level. In this study, we quantify the influence of both solvation models on folding stability at the individual backbone and side chain resolutions. We assess the residue-specific folding free energy components of a ß-sheet protein and a helical protein using trajectories resulting from TIP3P explicit and generalized Born/surface area implicit solvent simulations of model proteins. We found that the thermodynamic discrepancy due to the implicit solvent mostly originates from charged side chains, followed by the under-stabilized hydrophobic ones. In contrast, the contributions of backbone residue in both proteins were comparable for explicit and implicit water models. Our study lays out the foundation for detailed thermodynamic assessment of solvation models in the context of protein simulation.

Selectively Enhanced Electrocatalytic Oxygen Evolution within Nanoscopic Channels Fitting a Specific Reaction Intermediate for Seawater Splitting.

Abundant availability of seawater grants economic and resource-rich benefits to water electrolysis technology requiring high-purity water if undesired reactions such as chlorine evolution reaction (CER) competitive to oxygen evolution reaction (OER) are suppressed. Inspired by a conceptual computational work suggesting that OER is kinetically improved via a double activation within 7 Å-gap nanochannels, RuO2 catalysts are realized to have nanoscopic channels at 7, 11, and 14 Å gap in average (dgap ), and preferential activity improvement of OER over CER in seawater by using nanochanneled RuO2 is demonstrated. When the channels are developed to have 7 Å gap, the OER current is maximized with the overpotential required for triggering OER minimized. The gap value guaranteeing the highest OER activity is identical to the value expected from the computational work. The improved OER activity significantly increases the selectivity of OER over CER in seawater since the double activation by the 7 Å-nanoconfined environments to allow an OER intermediate (*OOH) to be doubly anchored to Ru and O active sites does not work on the CER intermediate (*Cl). Successful operation of direct seawater electrolysis with improved hydrogen production is demonstrated by employing the 7 Å-nanochanneled RuO2 as the OER electrocatalyst.

Graphene Quantum Dots Alleviate Impaired Functions in Niemann-Pick Disease Type C in Vivo.

While the neuropathological characteristics of Niemann-Pick disease type C (NPC) result in a fatal diagnosis, the development of clinically available therapeutic agent remains a challenge. Here we propose graphene quantum dots (GQDs) as a potential candidate for the impaired functions in NPC in vivo. In addition to the previous findings that GQDs exhibit negligible long-term toxicity and are capable of penetrating the blood-brain barrier, GQD treatment reduces the aggregation of cholesterol in the lysosome through expressed physical interactions. GQDs also promote autophagy and restore defective autophagic flux, which, in turn, decreases the atypical accumulation of autophagic vacuoles. More importantly, the injection of GQDs inhibits the loss of Purkinje cells in the cerebellum while also demonstrating reduced activation of microglia. The ability of GQDs to alleviate impaired functions in NPC proves the promise and potential of the use of GQDs toward resolving NPC and other related disorders.

Electron Attachment to the (O2···CO2) van der Waals Complex Results in a Monomeric Anion (O2-CO2)-, a Possible Form of CO4.

We found that electron attachment to the van der Waals complex (O2···CO2) turns the weak intermolecular bond into a pseudochemical bond of significant strength. The resulting monomeric molecular anion (O2-CO2)- may be a form of CO4-, the gaseous anionic species suspected to be present in Earth's ionosphere whose chemical characteristics have not been comprehensively identified since its existence was first predicted by Conway in 1962. The measured vertical detachment energy of CO4- is very large (4.56 ± 0.05 eV), while the known electron affinity of its component species is much smaller (0.448 eV, O2) or even negative (-0.6 eV, CO2). These characteristics are correctly borne out by theoretical calculations that show that electron attachment transforms the van der Waals complex to a single contiguous molecular anion, with the formation of a pseudochemical bond between O2 and CO2 through an extended π-orbital system.

Control defeasance by anti-alignment in the excited state.

We predict anti-alignment dynamics in the excited state of H2+ or related homonuclear dimers in the presence of a strong field. This effect is a general indirect outcome of the strong transition dipole and large polarizabilities typically used to control or to induce alignment in the ground state. In the excited state, however, the polarizabilities have the opposite sign compared to those in the ground state, generating a torque that aligns the molecule perpendicular to the field, deeming any laser-control strategy impossible.

Grid-Based Ehrenfest Model To Study Electron-Nuclear Processes.

The two-dimensional electron-nuclear Schrödinger equation using soft-core Coulomb potentials has been a cornerstone for modeling and predicting the behavior of one-active-electron diatomic molecules, particularly for processes where both bound and continuum states are important. The model, however, is computationally expensive to extend to more electron or nuclear coordinates. Here we propose use of the Ehrenfest approach to treat the nuclear motion, while the electronic motion is still solved by quantum propagation on a grid. In this work, we present results for a one-dimensional treatment of H2+, where the quantum and semiclassical dynamics can be directly compared, showing remarkably good agreement for a variety of situations. The advantage of the Ehrenfest approach is that it can be easily extended to treat as many nuclear degrees of freedom as needed.

Conformational sampling of metastable states: Tq-REM as a novel replica exchange method.

Although the replica exchange methods (REMs) were developed as efficient conformational sampling methods for bio-molecular simulations, their application to very large bio-systems is somewhat limited. We propose a new replica exchange scheme (Tq-REM) created by combining the conventional temperature-REM (T-REM) and one of the Hamiltonian-REMs, q-REM, using the effective potential with reduced barriers. In the proposed Tq-REM scheme, high temperature replicas in T-REM are substituted with q-replicas. This combined scheme is expected to exploit advantages of the T-REM and q-REM resulting in improved sampling efficiency while minimizing the drawbacks of both approaches. We investigated the performance of Tq-REM compared with T-REM by performing all-atom MD simulations on Met-enkephalin, (AAQAA)3, and Trpzip2. It was found that convergence of the free energy surfaces was improved by Tq-REM over the conventional T-REM. In particular, the trajectories of Tq-REM were able to sample the relevant conformations for all of the metastable folding intermediates, while some of the local minimum structures are poorly represented by T-REM. The results of the present study suggest that Tq-REM can provide useful tools to investigate systems where metastable states play important roles.

Site-dependent effects of methylation on the electronic spectra of jet-cooled methylated xanthine compounds.

We obtained the electronic spectra of various methylated xanthine compounds including caffeine in a supersonic jet by resonant two-photon ionization spectroscopy. The methyl group in the tested methylated xanthine compounds has a distinct, site-dependent effect on the electronic spectrum. Methylation at the N3 position causes a significant red shift of the ππ* state, whereas methylation at the N1 position has only minimal effects on the electronic spectrum. The notably broad spectra of theobromine and caffeine result from methyl substitution at the N7 position, which causes a large displacement between the potential energy surfaces of the S0 and S1 states, and a strong vibronic coupling. We also investigated the internal rotation of the methyl group and its effect on the electronic spectrum of the methylated xanthine compounds. We found that the barrier height for the torsional motion in the ground state is significantly affected by a carbonyl or methyl group that lies close to the methyl group of interest. In contrast, the torsional barrier in the excited state is governed by the hyperconjugation interaction in the lowest unoccupied molecular orbital. The agreement between the experimental and simulated spectra of torsional vibronic bands suggested that the low frequency torsional vibrations arising from the tunneling splitting and the coupling between the torsional and molecular motions give theobromine and theophylline the multiplet nature of their origin bands. This study provides a new level of understanding for the methyl substitution effects on the electronically excited states of xanthine compounds, which may very well be applicable to many other methyl substituted biomolecules including DNAs and proteins.

Geometrical Optimization Approach to Isomerization: Models and Limitations.

We study laser-driven isomerization reactions through an excited electronic state using the recently developed Geometrical Optimization procedure. Our goal is to analyze whether an initial wave packet in the ground state, with optimized amplitudes and phases, can be used to enhance the yield of the reaction at faster rates, driven by a single picosecond pulse or a pair of femtosecond pulses resonant with the electronic transition. We show that the symmetry of the system imposes limitations in the optimization procedure, such that the method rediscovers the pump-dump mechanism.

"Stirred, Not Shaken": Vibrational Coherence Can Speed Up Electronic Absorption.

We have recently proposed a laser control scheme for ultrafast absorption in multilevel systems by parallel transfer (J. Phys. Chem. Lett. 2015, 6, 1724). In this work we develop an analytical model that better takes into account the main features of electronic absorption in molecules. We show that the initial vibrational coherence in the ground electronic state can be used to greatly enhance the rate and yield of absorption when ultrashort pulses are used, provided that the phases of the coherences are taken into account. On the contrary, the initial coherence plays no role in the opposite limit, when a single long pulse drives the optical transition. The theory is tested by numerical simulations in the first absorption band of Na2.

Multiscale modeling of macromolecular biosystems.

In this article, we review the recent progress in multiresolution modeling of structure and dynamics of protein, RNA and their complexes. Many approaches using both physics-based and knowledge-based potentials have been developed at multiple granularities to model both protein and RNA. Coarse graining can be achieved not only in the length, but also in the time domain using discrete time and discrete state kinetic network models. Models with different resolutions can be combined either in a sequential or parallel fashion. Similarly, the modeling of assemblies is also often achieved using multiple granularities. The progress shows that a multiresolution approach has considerable potential to continue extending the length and time scales of macromolecular modeling.

Statistical torsion angle potential energy functions for protein structure modeling: a bicubic interpolation approach.

A set of grid type knowledge-based energy functions is introduced for ϕ-χ1 , ψ-χ1 , ϕ-ψ, and χ1 -χ2 torsion angle combinations. Boltzmann distribution is assumed for the torsion angle populations from protein X-ray structures, and the functions are named as statistical torsion angle potential energy functions. The grid points around periodic boundaries are duplicated to force periodicity, and the remedy relieves the derivative discontinuity problem. The devised functions rapidly improve the quality of model structures. The potential bias in the functions and the usefulness of additional secondary structure information are also investigated. The proposed guiding functions are expected to facilitate protein structure modeling, such as protein structure prediction, protein design, and structure refinement.

Two-pulse control of large-amplitude vibrations in H2(+).

A laser-adiabatic manipulation of the bond (LAMB) scheme using moderately intense fields is proposed to induce and control large-amplitude oscillations in nuclear wave packets. The present scheme involves an ultrashort UV pump pulse to initially create a wave packet in an excited electronic state of the hydrogen molecular ion and a low-frequency control pulse, which is switched on after a given time, leading to controllable vibrational trapping. The choice of H2(+) as the target exploits the larger dipole values that molecular ions present as the internuclear distance increases. The amplitude and oscillation period of the wave packet is tuned by the field parameters of the control pulse, and more importantly, significant dissociation and ionization losses are prevented by keeping the laser intensities below hundreds of Terawatts. Our numerical simulations, based on the solution of the time-dependent Schrödinger equation, show that this control of the bond length is achieved in a wide range of moderate intensities and for relatively long pulse durations, from tens to hundreds of femtoseconds.

Ultrafast coherent control of giant oscillating molecular dipoles in the presence of static electric fields.

We propose a scheme to generate electric dipole moments in homonuclear molecular cations by creating, with an ultrashort pump pulse, a quantum superposition of vibrational states on electronic states strongly perturbed by very strong static electric fields. By field-induced molecular stabilization, the dipoles can reach values as large as 50 Debyes and oscillate on a time-scale comparable to that of the slow vibrational motion. We show that both the electric field and the pump pulse parameters can be used to control the amplitude and period of the oscillation, while preventing the molecule from ionizing or dissociating.

In silico investigation of the structural stability as the origin of the pathogenicity of α-synuclein protofibrils.

α-Synuclein is a presynaptic neuronal protein. The fibril form of α-synuclein is a major constituent of the intraneuronal inclusion called Lewy body, a characteristic hallmark of Parkinson's disease. Recent ssNMR and cryo-EM experiments of wild-type α-synuclein fibrils have shown polymorphism and observed two major polymorphs, rod and twister. To associate the cytotoxicity of α-synuclein fibrils with their structural features, it is essential to understand the origins of their structural stability. In this study, we performed molecular dynamics simulations of the two major polymorphs of wild-type α-synuclein fibrils. The predominance of specific fibril polymorphs was rationalized in terms of relative structural stability in aqueous environments, which was attributed to the cooperative contributions of various stabilizing features. The results of the simulations indicated that highly stable structures in aqueous environments could be maintained by the cooperation of compact sidechain packing in the hydrophobic core, backbone geometry of the maximal ß-sheet content wrapping the hydrophobic core, and solvent-exposed sidechains with large fluctuations maximizing the solvation entropy. The paired structure of the two protofilaments provides additional stability, especially at the interface region, by forming steric zipper interactions and hiding the hydrophobic residues from exposure to water. The sidechain interaction analyses and pulling simulations showed that the rod polymorph has stronger sidechain interactions and exhibits higher dissociation energy than the twister polymorph. It is expected that our study will provide a basis for understanding the pathogenic behaviors of diverse amyloid strains in terms of their structural properties.Communicated by Ramaswamy H. Sarma.

Two-qubit atomic gates: spatio-temporal control of Rydberg interaction.

By controlling the temporal and spatial features of light, we propose a novel protocol to prepare two-qubit entangling gates on atoms trapped at close distance, which could potentially speed up the operation of the gate from the sub-micro to the nanosecond scale. The protocol is robust to variations in the pulse areas and the position of the atoms, by virtue of the coherent properties of a dark state, which is used to drive the population through Rydberg states. From the time-domain perspective, the protocol generalizes the one proposed by Jaksch and coworkers [Jaksch et al., Phys. Rev. Lett., 2000, 85, 2208], with three pulses that operate symmetrically in time, but with different pulse areas. From the spatial-domain perspective, it uses structured light. We analyze the map of the gate fidelity, which forms rotated and distorted lattices in the solution space. Finally, we study the effect of an additional qubit to the gate performance and propose generalizations that operate with multi-pulse sequences.

A simplified homology-model builder toward highly protein-like structures: an inspection of restraining potentials.

A homology model builder using simple restraining potentials based on spline-interpolated quadratic functions is developed and interfaced with CHARMM package. The continuity and stability of the potential function were validated, and the parameters were optimized using the CASP7 targets. The performance of the model builder was benchmarked to the Modeller program using the template-based modeling targets in CASP9. The benchmark results show that, while our builder yields the structures with slightly lower packing, backbone, and template modeling scores, our models show much better protein-like scores in terms of normalized discrete optimized protein energy, dipolar distance-scaled finite-ideal gas reference, Molprobity clash, Ramachandran appearance Z-score, and rotamer Z-score. As our model builder is interfaced with CHARMM, it is advantageous to directly use other CHARMM functionality and energy functions to refine the model structures or to use the models for other computational studies using CHARMM.

Ultrafast control of the internuclear distance with parabolic chirped pulses.

Recently, control over the bond length of a diatomic molecule with the use of parabolic chirped pulses was predicted on the basis of numerical calculations [Chang; et al. Phys. Rev. A 2010, 82, 063414]. To achieve the required bond elongation, a laser scheme was proposed that implies population inversion and vibrational trapping in a dissociative state. In this work we identify two regimes where the scheme works, called the strong and the weak adiabatic regimes. We define appropriate parameters to identify the thresholds where the different regimes operate. The strong adiabatic regime is characterized by a quasi-static process that requires longer pulses. The molecule is stabilized at a bond distance and at a time directly controlled by the pulse in a time-symmetrical way. In this work we analyze the degree of control over the period and elongation of the bond as a function of the pulse bandwidth. The weak adiabatic regime implies dynamic deformation of the bond, which allows for larger bond stretch and the use of shorter pulses. The dynamics is anharmonic and not time-symmetrical and the final state is a wave packet in the ground potential. We show how the vibrational energy of the wave packet can be controlled by changing the pulse duration.

Relativistic potential energy surfaces of initial oxidations of Si(100) by atomic oxygen: the importance of surface dimer triplet state.

The non-relativistic and relativistic potential energy surfaces (PESs) of the symmetric and asymmetric reaction paths of Si(100)-2×1 oxidations by atomic oxygen were theoretically explored. Although only the singlet PES turned out to exist as a major channel leading to "on-dimer" product, both the singlet and triplet PESs leading to "on-top" products are attractive. The singlet PESs leading to the two surface products were found to be the singlet combinations (open-shell singlet) of the low-lying triplet state of surface silicon dimer and the ground (3)P state of atomic oxygen. The triplet state of the "on-top" product can also be formed by the ground singlet state of the surface silicon dimer and the same (3)P oxygen. The attractive singlet PESs leading to the "on-dimer" and "on-top" products made neither the intersystem crossings from triplet to singlet PES nor high energy (1)D of atomic oxygen necessary. Rather, the low-lying triplet state of surface silicon dimer plays an important role in the initial oxidations of silicon surface.

Mutation effects on FAS1 domain 4 based on structure and solubility.

Mutations in the fasciclin 1 domain 4 (FAS1-4) of transforming growth factor ß-induced protein (TGFBIp) are associated with insoluble extracellular deposits and corneal dystrophies (CDs). The decrease in solubility upon mutation has been implicated in CD; however, the exact molecular mechanisms are not well understood. Here, we performed molecular dynamics simulations followed by solvation thermodynamic analyses of the FAS1-4 domain and its three mutants-R555W, R555Q, and A546T-linked to granular corneal dystrophy type 1, Thiel-Behnke corneal dystrophy and lattice corneal dystrophy, respectively. We found that both R555W and R555Q mutants have less affinity toward solvent water relative to the wild-type protein. In the R555W mutant, a remarkable increase in solvation free energy was observed because of the structural changes near the mutation site. The mutation site W555 is buried in other hydrophobic residues, and R557 simultaneously forms salt bridges with E554 and D561. In the R555Q mutant, the increase in solvation free energy is caused by structural rearrangements far from the mutation site. R558 separately forms salt bridges with D575, E576, and E598. Thus, we thus identified the relationship between the decrease in solubility and conformational changes caused by mutations, which may be useful in designing potential therapeutics and in blocking FAS1 aggregation related to CD.