Protein-ligand docking against non-native protein conformers

In the validation of protein-ligand docking protocols, performance is mostly measured against native protein conformers, i.e. each ligand is docked into the protein conformation from the structure that contained that ligand. In real-life applications, however, ligands are docked against non-native conformations of the protein, i.e. the apo structure or a structure of a different protein-ligand complex. Here, we have constructed an extensive test set for assessing docking performance against non-native protein conformations. This new test set is built on the Astex Diverse Set (which we recently constructed for assessing native docking performance) and contains 1112 non-native structures for 65 drug targets. Using the protein-ligand docking program GOLD, the Astex Diverse Set and the new Astex Non-native Set, we established that, whereas docking performance (top-ranked solution within 2 A rmsd of the experimental binding mode) is approximately 80% for native docking, this drops to 61% for non-native docking. A similar drop-off is observed for sampling performance (any solution within 2 A): 91% for native docking vs 72% for non-native docking. No significant differences were observed between docking performance against apo and nonapo structures. We found that, whereas small variations in protein conformation are generally tolerated by our rigid docking protocol, larger protein movements result in a catastrophic drop-off in performance. Some docking performance and nearly all sampling performance can be recovered by considering dockings produced against a small number of non-native structures simultaneously. Docking against non-native structures of complexes containing ligands that are similar to the docked ligand also significantly improves both docking performance and sampling performance.     

非天然相互作用对均聚多肽链螺旋形成动力学过程的影响的计算机模拟研究

以螺旋结构的形成过程为研究对象,基于粗粒化的格子模型和动态蒙特卡罗模拟方法,初步探讨了非天然氢键相互作用对均聚多肽链螺旋折叠动力学过程的影响.研究发现,非天然氢键的引入虽然延缓了其热力学转变的发生,但也从整体上降低了折叠动力学过程的能垒,在某一特定温度之下,反而可以提高折叠速率.对其折叠路径分布的分析表明,非天然氢键可以减少慢速折叠路径的发生,而后者是导致折叠时间增加的主要因素.另一方面,比较特定温度下多肽链链构象及螺旋片断随时间的演化进程,发现非天然氢键在一定程度上影响了天然氢键的形成以及天然态构象的稳定存在,同时也加快了其部分解折叠过程.这说明,非天然相互作用的存在有利于蛋白质构象的快速动态调整,从而行使其相应的生物功能.     

Interplay of secondary structures and side-chain contacts in the denatured state of BBA1

The denatured state of a miniprotein BBA1 is studied under the native condition with the AMBER/Poisson-Boltzmann energy model and with the self-guided enhanced sampling technique. Forty independent trajectories are collected to sample the highly diversified denatured structures. Our simulation data show that the denatured BBA1 contains high percentage of native helix and native turn, but low percentage of native hairpin. Conditional population analysis indicates that the native helix formation and the native hairpin formation are not cooperative in the denatured state. Side-chain analysis shows that the native hydrophobic contacts are more preferred than the non-native hydrophobic contacts in the denatured BBA1. In contrast, the salt-bridge contacts are more or less nonspecific even if their populations are higher than those of hydrophobic contacts. Analysis of the trajectories shows that the native helix mostly initiates near the N terminus and propagates to the C terminus, and mostly forms from 3(10)-helix/turn to alpha helix. The same analysis shows that the native turn is important but not necessary in its formation in the denatured BBA1. In addition, the formations of the two strands in the native hairpin are rather asymmetric, demonstrating the likely influence of the protein environment. Energetic analysis shows that the native helix formation is largely driven by electrostatic interactions in denatured BBA1. Further, the native helix formation is associated with the breakup of non-native salt-bridge contacts and the accumulation of native salt-bridge contacts. However, the native hydrophobic contacts only show a small increase upon the native helix formation while the non-native hydrophobic contacts stay essentially the same, different from the evolution of hydrophobic contacts observed in an isolated helix folding.     

Assessment of Semiempirical Quantum Mechanical Methods for the Evaluation of Protein Structures

The ability to discriminate native structures from computer-generated misfolded ones is key to predicting the three-dimensional structure of a protein from its amino acid sequence. Here we describe an assessment of semiempirical methods for discriminating native protein structures from decoy models. The discrimination of decoys entails an analysis of a large number of protein structures, and provides a large-scale validation of quantum mechanical methods and their ability to accurately model proteins. We combine our analysis of semiempirical methods with a comparison of an AMBER force field to discriminate decoys in conjunction with a continuum solvent model. Protein decoys provide a rigorous and reliable benchmark for the evaluation of scoring functions, not only in their ability to accurately identify native structures but also to be computationally tractable to sample a large set of non-native models.     

Cooperative alpha-helix formation of beta-lactoglobulin induced by sodium n-alkyl sulfates

It is generally assumed that folding intermediates contain partially formed native-like secondary structures. However, if we consider the fact that the conformational stability of the intermediate state is simpler than that of the native state, it would be expected that the secondary structures in a folding intermediate would not necessarily be similar to those of the native state. beta-Lactoglobulin is a predominantly beta-sheet protein, although it has a markedly high intrinsic preference for alpha-helical structure. The formation of non-native alpha-helical intermediate of beta-lactoglobulin was induced by n-alkyl sulfates including sodium octyl sulfate, SOS; sodium decyl sulfate, SDeS; sodium dodecyl sulfate, SDS; and sodium tetradecyl sulfate, STS at special condition. The effect of n-alkyl sulfates on the structure of native beta-lactoglobulin at pH 2 was utilized to investigate the contribution of hydrophobic interactions to the stability of non-native alpha-helical intermediate. The addition of various concentrations of n-alkyl sulfates to the native state of beta-lactoglobulin (pH 2) appears to support the stabilized form of non-native alpha-helical intermediate at pH 2. The m values of the intermediate state of beta-lactoglobulin by SOS, SDeS, SDS and STS showed substantial variation. The enhancement of m values as the stability criterion of non-native alpha-helical intermediate state corresponded with increasing chain length of the cited n-alkyl sulfates. The present results suggest that the folding reaction of beta-lactoglobulin follows a non-hierarchical mechanism and hydrophobic interactions play important roles in stabilizing the non-native alpha-helical intermediate state.     

无机纳米晶的形貌调控及生长机理研究

形貌及尺寸规整可控的纳米晶体的合成是目前十分引人注目的纳米材料研究领域．制备合成中的形貌调控及其功能化是这些纳米材料能够得到应用的关键问题．研究者们希望在纳米晶的任一阶段均能实现控制并在期望的阶段停止,从而得到尺寸、形态、结构及组成确定的纳米晶体．本文综述了近年来无机纳米晶体的典型合成路径,深入探讨了纳米晶在成核、生长及熟化阶段的控制原理,研究了液相合成纳米材料过程中晶体结构与生长行为的相关性问题,并总结了几类具有代表性的低维、多维纳米晶体的形成规律和生长机理．探索纳米粒子的调控合成对于纳米材料的规模化生产及应用具有重要的理论价值和指导意义．     

Supramolecular chlorophyll aggregates inspired from specific light-harvesting antenna “chlorosome”: Static nanostructure,dynamic construction process,and versatile application

Photosynthetic light-harvesting antennas possess a variety of supramolecular structures with the same function (collecting sunlight energy), dependent on their living habitats and environments of phototrophs. Notably, the main antenna in green photosynthetic bacteria called “chlorosome” is structurally unique. Its core is constructed solely from self-aggregates of chlorophyll molecules without the support of any protein scaffolds. The supramolecular structures of the chlorophyll aggregates were already estimated, but have not been determined completely due to the natural diversity of chlorosomes. The static structures of chlorosomes are somewhat difficult to be characterized, and also the determination of their dynamic construction processes in vivo, such as their biogenesis and growth, is more challenging. Consequently, the measurement and observation of a simplified chlorosome model prepared by in vitro self-assembly of native or non-native (semisynthetic) chlorophylls are important. The present review focuses on evaluation of the static and dynamic nanostructures of chlorosomal aggregates. The construction, observation, and analysis of such models could be translated into the supramolecular aggregates of native chlorosomes. Additionally, synthetic aggregates display remarkable properties, which would be valuable for the development of solar cells and artificial photosynthesis. Such systems could potentially also be applied as photofunctional materials.     

Facile "green" synthesis, characterization, and catalytic function of beta-D-glucose-stabilized Au nanocrystals

We present a straightforward, economically viable, and "green" approach for the synthesis and stabilization of relatively monodisperse Au nanocrystals with an average diameter of 8.2 nm (standard deviation, SD=2.3 nm) by using nontoxic and renewable biochemical of beta-D-glucose and by simply adjusting the pH environment in aqueous medium. The beta-D-glucose acts both as reducing agent and capping agent for the synthesis and stabilization of Au nanocrystals in the system. The UV/Vis spectroscopy, Fourier transform infrared (FT-IR) spectroscopy, transmission electron microscopy (TEM), electron diffraction (ED), and X-ray diffraction (XRD) techniques were employed to systematically characterize Au nanocrystals synthesized. Additionally, it is shown that these beta-D-glucose-stabilized Au nanocrystals function as effective catalyst for the reduction of 4-nitrophenol in the presence of NaBH4 (otherwise unfeasible if only the strong reducing agent NaBH4 is employed), which was reflected by the UV/Vis spectra of the catalytic reaction kinetics.     

Thermodynamics of folding and association of lattice-model proteins

Closely related to the "protein folding problem" is the issue of protein misfolding and aggregation. Protein aggregation has been associated with the pathologies of nearly 20 human diseases and presents serious difficulties during the manufacture of pharmaceutical proteins. Computational studies of multiprotein systems have recently emerged as a powerful complement to experimental efforts aimed at understanding the mechanisms of protein aggregation. We describe the thermodynamics of systems containing two lattice-model 64-mers. A parallel tempering algorithm abates problems associated with glassy systems and the weighted histogram analysis method improves statistical quality. The presence of a second chain has a substantial effect on single-chain conformational preferences. The melting temperature is substantially reduced, and the increase in the population of unfolded states is correlated with an increase in interactions between chains. The transition from two native chains to a non-native aggregate is entropically favorable. Non-native aggregates receive approximately 25% of their stabilizing energy from intraprotein contacts not found in the lowest-energy structure. Contact maps show that for non-native dimers, nearly 50% of the most probable interprotein contacts involve pairs of residues that form native contacts, suggesting that a domain-swapping mechanism is involved in self-association.     

Surface Capping Agents and Their Roles in Shape‐Controlled Synthesis of Colloidal Metal Nanocrystals

Surface capping agents have been extensively used to control the evolution of seeds into nanocrystals with diverse but well‐controlled shapes. Here we offer a comprehensive review of these agents, with a focus on the mechanistic understanding of their roles in guiding the shape evolution of metal nanocrystals. We begin with a brief introduction to the early history of capping agents in electroplating and bulk crystal growth, followed by discussion of how they affect the thermodynamics and kinetics involved in a synthesis of metal nanocrystals. We then present representative examples to highlight the various capping agents, including their binding selectivity, molecular‐level interaction with a metal surface, and impacts on the growth of metal nanocrystals. We also showcase progress in leveraging capping agents to generate nanocrystals with complex structures and/or enhance their catalytic properties. Finally, we discuss various strategies for the exchange or removal of capping agents, together with perspectives on future directions.     

Folding transition-state and denatured-state ensembles of FSD-1 from folding and unfolding simulations

Characterization of the folding transition-state ensemble and the denatured-state ensemble is an important step toward a full elucidation of protein folding mechanisms. We report herein an investigation of the free-energy landscape of FSD-1 protein by a total of four sets of folding and unfolding molecular dynamics simulations with explicit solvent. The transition-state ensemble was initially identified from unfolding simulations at 500 K and was verified by simulations at 300 K starting from the ensemble structures. The denatured-state ensemble and the early-stage folding were studied by a combination of unfolding simulations at 500 K and folding simulations at 300 K starting from the extended conformation. A common feature of the transition-state ensemble was the substantial formation of the native secondary structures, including both the alpha-helix and beta-sheet, with partial exposure of the hydrophobic core in the solvent. Both the native and non-native secondary structures were observed in the denatured-state ensemble and early-stage folding, consistent with the smooth experimental melting curve. Interestingly, the contact orders of the transition-state ensemble structures were similar to that of the native structure and were notably lower than those of the compact structures found in early-stage folding, implying that chain and topological entropy might play significant roles in protein folding. Implications for FSD-1 folding mechanisms and the rate-limiting step are discussed. Analyses further revealed interesting non-native interactions in the denatured-state ensemble and early-stage folding and the possibility that destabilization of these interactions could help to enhance the stability and folding rate of the protein.     

A free-energy landscape for coupled folding and binding of an intrinsically disordered protein in explicit solvent from detailed all-atom computations

The N-terminal repressor domain of neural restrictive silencer factor (NRSF) is an intrinsically disordered protein (IDP) that binds to the paired amphipathic helix (PAH) domain of mSin3. An NMR experiment revealed that the minimal binding unit of NRSF is a 15-residue segment that adopts a helical structure upon binding to a cleft of mSin3. We computed a free-energy landscape of this system by an enhanced conformational sampling method, all-atom multicanonical molecular dynamics. The simulation started from a configuration where the NRSF segment was fully disordered and distant from mSin3 in explicit solvent. In the absence of mSin3, the disordered NRSF segment thermally fluctuated between hairpins, helices, and bent structures. In the presence of mSin3, the segment bound to mSin3 by adopting the structures involved in the isolated state, and non-native and native complexes were formed. The free-energy landscape comprised three superclusters, and free-energy barriers separated the superclusters. The native complex was located at the center of the lowest free-energy cluster. When NRSF landed in the largest supercluster, the generated non-native complex moved on the landscape to fold into the native complex, by increasing the interfacial hydrophobic contacts and the helix content. When NRSF landed in other superclusters, the non-native complex overcame the free-energy barriers between the various segment orientations in the binding cleft of mSin3. Both population-shift and induced-fit (or induced-folding) mechanisms work cooperatively in the coupled folding and binding. The diverse structural adaptability of NRSF may be related to the hub properties of the IDP.     

Fast Synthesis of PbS Nanocrystals in Aqueous Solution with Shape Evolution from Cubic to Octahedral Structures and Their Assembled Structures

In this study, we have developed for the first time a fast and energy‐efficient method for the synthesis of PbS nanocrystals with systematic shape evolution from cubic to truncated cubic, cuboctahedral, truncated octahedral, and octahedral structures. The method involves the addition of a small volume of preheated lead acetate and thioacetamide (TAA) mixture to an aqueous growth solution of lead acetate, thioacetamide, cetyltrimethylammonium bromide, and nitric acid. By varying the amount of thioacetamide added to the growth solution, PbS nanocrystals with different morphologies were generated in 2 h at 90 °C. Slight experimental modifications were adopted to generate truncated octahedra. The nanocrystals have very uniform dimensions with average sizes of 32–47 nm. Their structures have been extensively examined by electron microscopy. Nanocube sizes can also be tuned within a range. UV/Vis absorption spectra of PbS cubes, cuboctahedra, and octahedra all show decreasing but continuous absorption from 300 nm to beyond 1000 nm. By monitoring the speed of darkening of solution color, particle growth rate was found to be fastest for nanocubes, followed by truncated cubes, cuboctahedra, and octahedra. These monodisperse nanocrystals can readily form self‐assembled structures. Truncated cubes and octahedra that form monolayer and multilayer packing arrangements have also been studied. This green approach to the synthesis of PbS nanocrystals with fine size and shape control should allow for investigations of their facet‐dependent properties and the fabrication of novel heterostructures.     

Metal nanocrystals with highly branched morphologies

Metal nanocrystals with highly branched morphologies are an exciting new class of nanomaterials owing to their unique structures, physicochemical properties, and great potential as catalysts, sensing materials, and building blocks for nanoscale devices. Various strategies have recently been developed for the solution-phase synthesis of metal nanocrystals with branched morphologies, such as multipods and nanodendrites. In this Minireview, the procedures and mechanisms underlying the formation of branched metal nanocrystals are presented in parallel with recent advances in synthetic approaches based on kinetically controlled overgrowth, aggregation-based growth, heterogeneous seeded growth, selective etching, and template-directed methods, as well as their properties for catalytic or electrocatalytic applications.     

Controlling the Size and Morphology of Au@Pd Core–Shell Nanocrystals by Manipulating the Kinetics of Seeded Growth

This article reports a systematic study of the seed‐mediated growth of Au@Pd core–shell nanocrystals with a variety of controlled sizes and morphologies. The key to the success of this synthesis is to manipulate the reaction kinetics by tuning a set of reaction parameters, including the type and concentration of capping agent, the amount of ascorbic acid used as the reducing agent, and the injection rate used for the precursor solution. Starting from Au nanospheres of 11 nm in diameter as the seeds, Au@Pd core–shell nanocrystals with a number of morphologies, including octahedra, concave octahedra, rectangular bars, cubes, concave cubes, and dendrites, could all be obtained by simply altering the reaction rate. For the first time, it was possible to generate Au@Pd nanocrystals with concave structures on the surfaces while their sizes were kept below 20 nm. In addition, the as‐prepared Au@Pd nanocubes can be used as seeds to generate Au@Pd@Au and Au@Pd@Au@Pd nanocrystals with multishelled structures.     

Controlling the size and morphology of Au@Pd core-shell nanocrystals by manipulating the kinetics of seeded growth

This article reports a systematic study of the seed-mediated growth of Au@Pd core-shell nanocrystals with a variety of controlled sizes and morphologies. The key to the success of this synthesis is to manipulate the reaction kinetics by tuning a set of reaction parameters, including the type and concentration of capping agent, the amount of ascorbic acid used as the reducing agent, and the injection rate used for the precursor solution. Starting from Au nanospheres of 11?nm in diameter as the seeds, Au@Pd core-shell nanocrystals with a number of morphologies, including octahedra, concave octahedra, rectangular bars, cubes, concave cubes, and dendrites, could all be obtained by simply altering the reaction rate. For the first time, it was possible to generate Au@Pd nanocrystals with concave structures on the surfaces while their sizes were kept below 20?nm. In addition, the as-prepared Au@Pd nanocubes can be used as seeds to generate Au@Pd@Au and Au@Pd@Au@Pd nanocrystals with multishelled structures.     

Seed‐Mediated Growth of Colloidal Metal Nanocrystals

Seed‐mediated growth is a powerful and versatile approach for the synthesis of colloidal metal nanocrystals. The vast allure of this approach mainly stems from the staggering degree of control one can achieve over the size, shape, composition, and structure of nanocrystals. These parameters not only control the properties of nanocrystals but also determine their relevance to, and performance in, various applications. The ingenuity and artistry inherent to seed‐mediated growth offer extensive promise, enhancing a number of existing applications and opening the door to new developments. This Review demonstrates how the diversity of metal nanocrystals can be expanded with endless opportunities by using seeds with well‐defined and controllable internal structures in conjunction with a proper combination of capping agent and reduction kinetics. New capabilities and future directions are also highlighted.     

Symmetry-controlled colloidal nanocrystals: nonhydrolytic chemical synthesis and shape determining parameters

Since inorganic nanocrystals exhibit unique shape-dependent nanoscale properties and can be utilized as basic building blocks for futuristic nanodevices, a systematic study on the shape control of these nanocrystals remains an important subject in materials and physical chemistry. In this feature article, we overview the recent progress on the synthetic development of symmetry-controlled colloidal nanocrystals of semiconductor and metal oxide, which are prepared through nonhydrolytic chemical routes. We describe their shape-guiding processes and illustrate the detailed key factors controlling their growth by examining various case studies of zero-dimensional spheres and cubes, one-dimensional rods, and quasi multidimensional structures such as disks, multipods, and stars. Specifically, the crystalline phase of nucleating seeds, surface energy, kinetic vs thermodynamic growth, and selective adhesion processes of capping ligands are found to be most crucial for the determination of the nanocrystal shape.