[Show abstract][Hide abstract] ABSTRACT: Rational design of molecular acceptors for non-fullerene organic solar cells remains challenging. Here we show that the introduction of two simple methyl groups on a bithiophene-bridged perylene diimide dimer leads to two molecular acceptors with distinctly different properties and solar cell performance. This work contributes towards understanding the structure-performance relationship of high-performance molecular acceptors. This journal is
Journal of Materials Chemistry A 09/2015; DOI:10.1039/C5TA05339K · 7.44 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Reference interaction site model (RISM) has recently become a popular approach in the study of thermodynamical and structural properties of the solvent around macromolecules. On the other hand, it was widely suggested that there exists water density depletion around large hydrophobic solutes (>1 nm), and this may pose a great challenge to the RISM theory. In this paper, we develop a new analytical theory, the Reference Interaction Site Model with Hydrophobicity induced density Inhomogeneity (RISM-HI), to compute solvent radial distribution function (RDF) around large hydrophobic solute in water as well as its mixture with other polyatomic organic solvents. To achieve this, we have explicitly considered the density inhomogeneity at the solute-solvent interface using the framework of the Yvon-Born-Green hierarchy, and the RISM theory is used to obtain the solute-solvent pair correlation. In order to efficiently solve the relevant equations while maintaining reasonable accuracy, we have also developed a new closure called the D2 closure. With this new theory, the solvent RDFs around a large hydrophobic particle in water and different water-acetonitrile mixtures could be computed, which agree well with the results of the molecular dynamics simulations. Furthermore, we show that our RISM-HI theory can also efficiently compute the solvation free energy of solute with a wide range of hydrophobicity in various water-acetonitrile solvent mixtures with a reasonable accuracy. We anticipate that our theory could be widely applied to compute the thermodynamic and structural properties for the solvation of hydrophobic solute.
The Journal of Chemical Physics 08/2015; 143(5):054110. DOI:10.1063/1.4928051 · 2.95 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Argonaute (Ago) proteins and microRNAs (miRNAs) are central components in RNA interference, which is a key cellular mechanism for sequence-specific gene silencing. Despite intensive studies, molecular mechanisms of how Ago recognizes miRNA remain largely elusive. In this study, we propose a two-step mechanism for this molecular recognition: selective binding followed by structural re-arrangement. Our model is based on the results of a combination of Markov State Models (MSMs), large-scale protein-RNA docking, and molecular dynamics (MD) simulations. Using MSMs, we identify an open state of apo human Ago-2 in fast equilibrium with partially open and closed states. Conformations in this open state are distinguished by their largely exposed binding grooves that can geometrically accommodate miRNA as indicated in our protein-RNA docking studies. miRNA may then selectively bind to these open conformations. Upon the initial binding, the complex may perform further structural re-arrangement as shown in our MD simulations and eventually reach the stable binary complex structure. Our results provide novel insights in Ago-miRNA recognition mechanisms and our methodology holds great potential to be widely applied in the studies of other important molecular recognition systems.
[Show abstract][Hide abstract] ABSTRACT: The RNA polymerase II (Pol II) is a eukaryotic enzyme that catalyzes the synthesis of the messenger RNA using a DNA template. Despite numerous biochemical and biophysical studies, it remains elusive whether the "secondary channel" is the only route for NTP to reach the active site of the enzyme or if the "main channel" could be an alternative. On this regard, crystallographic structures of Pol II have been extremely useful to understand the structural basis of transcription, however, the conformation of the unpaired non-template DNA part of the full transcription bubble (TB) is still unknown. Since diffusion routes of the nucleoside triphosphate (NTP) substrate through the main channel might overlap with the TB region, gaining structural information of the full TB is critical for a complete understanding of Pol II transcription process. In this study, we have built a structural model of Pol II with a complete transcription bubble based on multiple sources of existing structural data and used Molecular Dynamics (MD) simulations together with structural analysis to shed light on NTP entry pathways. Interestingly, we found that although both channels have enough space to allow NTP loading, the percentage of MD conformations containing enough space for NTP loading through the secondary channel is twice higher than that of the main channel. Further energetic study based on MD simulations with NTP loaded in the channels has revealed that the diffusion of the NTP through the main channel is greatly disfavored by electrostatic repulsion between the NTP and the highly negatively charged backbones of nucleotides in the non-template DNA strand. Taken together, our results suggest that the secondary channel is the major route for NTP entry during Pol II transcription.
[Show abstract][Hide abstract] ABSTRACT: Thalassospiramides comprise a large family of lipopeptide natural products produced by Thalassospira and Tistrella marine bacteria. Here we provide further evidence of their nanomolar inhibitory activity against the human calpain 1 protease. Analysis of structure-activity relationship data supported our hypothesis that the rigid 12-membered ring containing an α,β-unsaturated carbonyl moiety is the pharmacologically active functional group, in contrast to classic electrophilic "warheads" in known calpain inhibitors. Using a combination of chemical modifications, mass spectrometric techniques, site-directed mutagenesis, and molecular modeling, we show the covalent binding of thalassospiramide's α,β-unsaturated carbonyl moiety to the thiol group of calpain's catalytic Cys115 residue by a Michael 1,4-addition reaction. As nanomolar calpain inhibitors with promising selectivity and low toxicity from natural sources are rare, we consider thalassospiramides as promising drug leads.
[Show abstract][Hide abstract] ABSTRACT: Bulk heterojunction (BHJ) organic solar cells (OSC) have attracted much research attention due to their promise in low cost conversion of solar energy. A common BHJ OSC consists of an electron donor and an electron acceptor that work together to convert light to electricity. Due to their highly twisted molecular structure, TPE-based molecules exhibit weak intermolecular interactions and thus excellent solubility in organic solvents even when they have no or very minimal alkyl-solubilizing groups. Given these properties, in this study, the TPE core structure is connected to four perylenediimide (PDI) units, which have a very large near-planar structure and are commonly used as the acceptor for non-fullerene OSCs. A key feature of SM acceptors compared with fullerenes is their excellent light absorption properties, which can be used to complement the absorption of the donor polymers.
[Show abstract][Hide abstract] ABSTRACT: Organic luminescent materials carrying no phenyl rings have attracted much interest from researchers due to their excellent biocompatibility and good biodegradability, which make them available for potential applications in a variety of biomedical areas, such as fluorescent bioprobe, drug delivery and gene carrier, and provide a new insight into the photophysical process of light emission. In this work, we studied the optical properties of poly[(maleic anhydride)-alt-(vinyl acetate)] (PMV), a pure oxygenic nonconjugated polymer and proved that the origin of its emission was associated with the clustering of the locked carbonyl groups. PMV exhibits solvatochromism: after interaction with electron-rich solvents, its absorption and emission shift to the longer wavelength region due to the formation of polymer/solvent complexes. This enables fine-tuning of its optical property by varying the solvent without the need of changing the chromophore.
[Show abstract][Hide abstract] ABSTRACT: The conformational dynamics of multibody systems plays crucial roles in many important problems. Markov state models (MSMs) are powerful kinetic network models that can predict long-time-scale dynamics using many short molecular dynamics simulations. Although MSMs have been successfully applied to conformational changes of individual proteins, the analysis of multibody systems is still a challenge because of the complexity of the dynamics that occur on a mixture of drastically different time scales. In this work, we have developed a new algorithm, automatic state partitioning for multibody systems (APM), for constructing MSMs to elucidate the conformational dynamics of multibody systems. The APM algorithm effectively addresses different time scales in the multibody systems by directly incorporating dynamics into geometric clustering when identifying the metastable conformational states. We have applied the APM algorithm to a 2D potential that can mimic a protein–ligand binding system and the aggregation of two hydrophobic particles in water and have shown that it can yield tremendous enhancements in the computational efficiency of MSM construction and the accuracy of the models.
Journal of Chemical Theory and Computation 01/2015; 11(1):17-27. DOI:10.1021/ct5007168 · 5.50 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: The RNA polymerase II elongation is central in eukaryotic transcription. Although multiple intermediates of the elongation complex have been identified, the dynamical mechanisms remain elusive or controversial. Here we build a structure-based kinetic model of a full elongation cycle of polymerase II, taking into account transition rates and conformational changes characterized from both single molecule experimental studies and computational simulations at atomistic scale. Our model suggests a force-dependent slow transition detected in the single molecule experiments corresponds to an essential conformational change of a trigger loop (TL) opening prior to the polymerase translocation. The analyses on mutant study of E1103G and on potential sequence effects of the translocation substantiate this proposal. Our model also investigates another slow transition detected in the transcription elongation cycle which is independent of mechanical force. If this force-independent slow transition happens as the TL gradually closes upon NTP binding, the analyses indicate that the binding affinity of NTP to the polymerase has to be sufficiently high. Otherwise, one infers that the slow transition happens pre-catalytically but after the TL closing. Accordingly, accurate determination of intrinsic properties of NTP binding is demanded for an improved characterization of the polymerase elongation. Overall, the study provides a working model of the polymerase II elongation under a generic Brownian ratchet mechanism, with most essential structural transition and functional kinetics elucidated.
[Show abstract][Hide abstract] ABSTRACT: Author Summary
Molecular recognition plays important roles in numerous biological processes including gene regulation, cell signaling and enzymatic activity. It has been suggested that molecular recognition employs a variety of mechanisms, ranging from induced fit to conformational selection. In many realistic systems, conformational selection and induced fit are not mutually exclusive. An analytical flux analysis has been developed to determine the contribution of each model, but it is extremely challenging to obtain the necessary kinetic parameters for this flux analysis through experimental techniques. In this work, we have developed an approach integrating Markov State Models, molecular dynamics simulations, and flux analysis to tackle this problem. Using this approach, we have quantified the recognition mechanism of the choline binding protein to be ∼90% conformational selection dominant in the experimental conditions. Our methodology provides a way to quantify the molecular recognition mechanisms that are extremely difficult to be directly accessed by experiments. This opens up numerous possibilities for in silico design to fine tune the recognition event either to increase the degree of conformational selection or induced fit, so that new properties could be created to accommodate the needs of protein engineering, drug development and beyond.
[Show abstract][Hide abstract] ABSTRACT: Nonenzymatic RNA polymerization in early life is likely to introduce backbone heterogeneity with a mixture of 2'-5' and 3'-5' linkages. On the other hand, modern nucleic acids are dominantly composed of 3'-5' linkages. RNA polymerase II (pol II) is a key modern enzyme responsible for synthesizing 3'-5'-linked RNA with high fidelity. It is not clear how modern enzymes, such as pol II, selectively recognize 3'-5' linkages over 2'-5' linkages of nucleic acids. In this work, we systematically investigated how phosphodiester linkages of nucleic acids govern pol II transcriptional efficiency and fidelity. Through dissecting the impacts of 2'-5' linkage mutants in the pol II catalytic site, we revealed that the presence of 2'-5' linkage in RNA primer only modestly reduces pol II transcriptional efficiency without affecting pol II transcriptional fidelity. In sharp contrast, the presence of 2'-5' linkage in DNA template leads to dramatic decreases in both transcriptional efficiency and fidelity. These distinct effects reveal that pol II has an asymmetric (strand-specific) recognition of phosphodiester linkage. Our results provided important insights into pol II transcriptional fidelity, suggesting essential contributions of phosphodiester linkage to pol II transcription. Finally, our results also provided important understanding on the molecular basis of nucleic acid recognition and genetic information transfer during molecular evolution. We suggest that the asymmetric recognition of phosphodiester linkage by modern nucleic acid enzymes likely stems from the distinct evolutionary pressures of template and primer strand in genetic information transfer during molecular evolution.
Proceedings of the National Academy of Sciences 07/2014; 111(32). DOI:10.1073/pnas.1406234111 · 9.67 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: One longstanding puzzle concerning photosystem II, a core component of photosynthesis, is that only one of the two symmetric branches in its reaction centre is active in electron transfer. To investigate the effect of the photosystem II environment on the preferential selection of the energy transfer pathway (a prerequisite for electron transfer), we have constructed an exciton model via extensive molecular dynamics simulations and quantum mechanics/molecular mechanics calculations based on a recent X-ray structure. Our results suggest that it is essential to take into account an ensemble of protein conformations to accurately compute the site energies. We identify the cofactor CLA606 of active chain as the most probable site for the energy excitation. We further pinpoint a number of charged protein residues that collectively lower the CLA606 site energy. Our work provides insights into the understanding of molecular mechanisms of the core machinery of the green-plant photosynthesis.
[Show abstract][Hide abstract] ABSTRACT: Alzheimer's disease (AD), characterized by cognitive decline, has emerged as a disease of synaptic failure. The present study reveals an unanticipated role of erythropoietin-producing hepatocellular A4 (EphA4) in mediating hippocampal synaptic dysfunctions in AD and demonstrates that blockade of the ligand-binding domain of EphA4 reverses synaptic impairment in AD mouse models. Enhanced EphA4 signaling was observed in the hippocampus of amyloid precursor protein (APP)/presenilin 1 (PS1) transgenic mouse model of AD, whereas soluble amyloid-β oligomers (Aβ), which contribute to synaptic loss in AD, induced EphA4 activation in rat hippocampal slices. EphA4 depletion in the CA1 region or interference with EphA4 function reversed the suppression of hippocampal long-term potentiation in APP/PS1 transgenic mice, suggesting that the postsynaptic EphA4 is responsible for mediating synaptic plasticity impairment in AD. Importantly, we identified a small-molecule rhynchophylline as a novel EphA4 inhibitor based on molecular docking studies. Rhynchophylline effectively blocked the EphA4-dependent signaling in hippocampal neurons, and oral administration of rhynchophylline reduced the EphA4 activity effectively in the hippocampus of APP/PS1 transgenic mice. More importantly, rhynchophylline administration restored the impaired long-term potentiation in transgenic mouse models of AD. These findings reveal a previously unidentified role of EphA4 in mediating AD-associated synaptic dysfunctions, suggesting that it is a new therapeutic target for this disease.
Proceedings of the National Academy of Sciences 06/2014; 111(27). DOI:10.1073/pnas.1405803111 · 9.67 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Transcription is a central step in gene expression, in which the DNA template is processively read by RNA polymerase II (Pol II), synthesizing a complementary messenger RNA transcript. At each cycle, Pol II moves exactly one register along the DNA, a process known as translocation. Although X-ray crystal structures have greatly enhanced our understanding of the transcription process, the underlying molecular mechanisms of translocation remain unclear. Here we use sophisticated simulation techniques to observe Pol II translocation on a millisecond timescale and at atomistic resolution. We observe multiple cycles of forward and backward translocation and identify two previously unidentified intermediate states. We show that the bridge helix (BH) plays a key role accelerating the translocation of both the RNA:DNA hybrid and transition nucleotide by directly interacting with them. The conserved BH residues, Thr831 and Tyr836, mediate these interactions. To date, this study delivers the most detailed picture of the mechanism of Pol II translocation at atomic level.
Proceedings of the National Academy of Sciences 04/2014; 111(21). DOI:10.1073/pnas.1315751111 · 9.67 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Conformational changes of proteins are an*Author contributed equally with all other contributors. essential part of many biological processes such as: protein folding, ligand binding, signal transduction, allostery, and enzymatic catalysis. Molecular dynamics (MD) simulations can describe the dynamics of molecules at atomic detail, therefore providing a much higher temporal and spatial resolution than most experimental techniques. Although MD simulations have been widely applied to study protein dynamics, the timescales accessible by conventional MD methods are usually limited to timescales that are orders of magnitude shorter than the conformational changes relevant for most biological functions. During the past decades great effort has been devoted to the development of theoretical methods that may enhance the conformational sampling. In recent years, it has been shown that the statistical mechanics framework provided by discrete-state and -time Markov State Models (MSMs) can predict long timescale dynamics from a pool of short MD simulations. In this chapter we provide the readers an account of the basic theory and selected applications of MSMs. We will first introduce the general concepts behind MSMs, and then describe the existing procedures for the construction of MSMs. This will be followed by the discussions of the challenges of constructing and validating MSMs, Finally, we will employ two biologically-relevant systems, the RNA polymerase and the LAO-protein, to illustrate the application of Markov State Models to elucidate the molecular mechanisms of complex conformational changes at biologically relevant timescales.
Advances in Experimental Medicine and Biology 01/2014; 805:29-66. DOI:10.1007/978-3-319-02970-2_2 · 1.96 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Molecular recognition, the process by which biological macromolecules selectively bind, plays an important role in many biological processes. Molecular simulations hold great potential to reveal the chemical details of molecular recognition and to complement experiments. However, it is challenging to reconstruct the binding process for two-body systems like protein-ligand complexes because the system's dynamics occurs on significantly different timescales due to several physical processes involved, such as diffusion, local interactions and conformational changes. In this chapter, we review some recent progress on applying Markov state models (MSMs) to two-body systems. Emphasis is placed on the value of projecting dynamics onto collective reaction coordinates and treating the ligand dynamics with different resolution models depending on the proximity of the protein and ligand. We also discuss some future directions on constructing MSMs to investigate molecular recognition processes.
Advances in Experimental Medicine and Biology 01/2014; 797:107-14. DOI:10.1007/978-94-007-7606-7_9 · 1.96 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: RNA polymerase is the enzyme that synthesizes RNA during the transcription process. To understand its mechanism, structural studies have provided us pictures of the series of steps necessary to add a new nucleotide to the nascent RNA chain, the steps altogether known as the nucleotide addition cycle (NAC). However, these static snapshots do not provide dynamic information of these processes involved in NAC, such as the conformational changes of the protein and the atomistic details of the catalysis. Computational studies have made efforts to fill these knowledge gaps. In this review, we provide examples of different computational approaches that have improved our understanding of the transcription elongation process for RNA polymerase, such as normal mode analysis, molecular dynamic (MD) simulations, Markov state models (MSMs). We also point out some unsolved questions that could be addressed using computational tools in the future.
Journal of Theoretical and Computational Chemistry 12/2013; 12(08):1341005. DOI:10.1142/S0219633613410058 · 0.64 Impact Factor