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Cheng, Xiaolin

Publications and source records attributed to Cheng, Xiaolin.

At least 73 records · Page 4
All sourcesNASA NTRSDOE OSTI
DOE OSTI2014

Structure and dynamics of a compact state of a multidomain protein, the mercuric ion reductase

Here, the functional efficacy of colocalized, linked protein domains is dependent on linker flexibility and system compaction. However, the detailed characterization of these properties in aqueous solution presents an enduring challenge. Here, we employ a novel, to our knowledge, combination of complementary techniques, including small-angle neutron scattering, neutron spin-echo spectroscopy, and all-atom molecular dynamics and coarse-grained simulation, to identify and characterize in detail the structure and dynamics of a compact form of mercuric ion reductase (MerA), an enzyme central to bacterial mercury resistance. MerA possesses metallochaperone-like N-terminal domains (NmerA) tethered to its catalytic core domain by linkers. The NmerA domains are found to interact principally through electrostatic interactions with the core, leashed by the linkers so as to subdiffuse on the surface over an area close to the core C-terminal Hg(II)-binding cysteines. How this compact, dynamical arrangement may facilitate delivery of Hg(II) from NmerA to the core domain is discussed.

59 BASIC BIOLOGICAL SCIENCES↗
DOE OSTI2014

Coarse-grain model for natural cellulose fibrils in explicit water

Understanding biomass structure and dynamics on multiple time and length scales is important for the development of cellulosic biofuels. To this aim, we have developed a coarse-grain (CG) model for molecular dynamics (MD) simulations of cellulose fibrils in explicit water based on target observables from fully atomistic simulations. This model examines the significance of the presence of explicit solvent and compares results with the previous, implicit solvent CG cellulose models. The present, constraint-free CG model is used to generate a series of noncrystalline fibril structures using a coupling parameter, λ, between fully crystalline and fully amorphous potentials. By exploring various structural parameters, including the root-mean-square deviation, root-mean-square fluctuations, radius of gyration, and persistence length, we find the crystalline-to-amorphous state transition takes place at λ ≈ 0.386. The persistence length of cellulose fibril in the transition region corresponds to that of native cellulose fibrils. The transition between crystalline and amorphous fibrils occurs at larger values of λ in explicit water than in the implicit case. Detailed analysis of individual energetic contribution to the transition reveals that the nonbonded interactions, in particular, that of cellulose water interaction, plays a significant role in the observed crystalline to amorphous transition of cellulose fibril. The present study thus highlights the importance of solvent presence that cannot be adequately described with the previous implicit solvent model. In conclusion, the present method provides an accurate and constraint-free approach for deriving a variety of structures of cellulose in water, with a wide range of crystallinity, suitable for incorporation into large-scale models of lignocellulosic biomass.

09 BIOMASS FUELS↗
DOE OSTI2014

The Molecular Structure of a Phosphatidylserine Bilayer Determined by Scattering and Molecular Dynamics Simulations

Phosphatidylserine (PS) lipids play essential roles in biological processes, including enzyme activation and apoptosis. We report on the molecular structure and atomic scale interactions of a fluid bilayer composed of 1-palmitoyl-2-oleoyl-sn-glycero-3-phosphatidylserine (POPS). A scattering density profile model, aided by molecular dynamics (MD) simulations, was developed to jointly refine different contrast small-angle neutron and X-ray scattering data, which yielded a lipid area of 62.7 A2 at 25 C. MD simulations with POPS lipid area constrained at different values were also performed using all-atom and aliphatic united-atom models. The optimal simulated bilayer was obtained using a model-free comparison approach. Examination of the simulated bilayer, which agrees best with the experimental scattering data, reveals a preferential interaction between Na+ ions and the terminal serine and phosphate moieties. Long-range inter-lipid interactions were identified, primarily between the positively charged ammonium, and the negatively charged carboxylic and phosphate oxygens. The area compressibility modulus KA of the POPS bilayer was derived by quantifying lipid area as a function of surface tension from area-constrained MD simulations. It was found that POPS bilayers possess a much larger KA than that of neutral phosphatidylcholine lipid bilayers. We propose that the unique molecular features of POPS bilayers may play an important role in certain physiological functions.

biomembranes↗
DOE OSTI2013

Impact of resistance mutations on inhibitor binding to HIV-1 integrase

Here, HIV-1 integrase (IN) is essential for HIV-1 replication, catalyzing two key reaction steps termed 3' processing and strand transfer. Therefore, IN has become an important target for antiviral drug discovery. However, mutants have emerged, such as E92Q/N155H and G140S/Q148H, which confer resistance to raltegravir (RAL), the first IN strand transfer inhibitor (INSTI) approved by the FDA, and to the recently approved elvitegravir (EVG). To gain insights into the molecular mechanisms of ligand binding and drug resistance, we performed molecular dynamics (MD) simulations of homology models of the HIV-1 IN and four relevant mutants complexed with viral DNA and RAL. The results show that the structure and dynamics of the 140s loop, comprising residues 140 to 149, are strongly influenced by the IN mutations. In the simulation of the G140S/Q148H double mutant, we observe spontaneous dissociation of RAL from the active site, followed by an intrahelical swing-back of the 3' -OH group of nucleotide A17, consistent with the experimental observation that the G140S/Q148H mutant exhibits the highest resistance to RAL compared to other IN mutants. An important hydrogen bond between residues 145 and 148 is present in the wild-type IN but not in the G140S/Q148H mutant, accounting for the structural and dynamical differences of the 140s' loop and ultimately impairing RAL binding in the double mutant. End-point free energy calculations that broadly capture the experimentally known RAL binding profiles elucidate the contributions of the 140s' loop to RAL binding free energies and suggest possible approaches to overcoming drug resistance.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2013

Enantioselective Electrophilic Trifluoromethylthiolation of β-Ketoesters: A Case of Reactivity and Selectivity Bias for Organocatalysis

A chiral Lewis base or a phase-transfer catalyst (PTC) can mediate the highly enantioselective trifluoromethylthiolation of β-ketoesters with the previously developed SCF 3 reagent (see scheme). Reactions of indanone-derived β-ketoesters occurred with high yield and excellent enantioselectivity with quinine as catalyst. In conclusion, reactions of tetralone- or 1-benzosuberone-derived β-ketoesters occurred with moderate to good enantioselectivity with a quinine-derived PTC.

37 INORGANIC, ORGANIC, PHYSICAL, AND ANALYTICAL CH↗
DOE OSTI2013

Ab Initio Study of Molecular Interactions in Cellulose Iα

Biomass recalcitrance, the resistance of cellulosic biomass to degradation, is due in part to the stability of the hydrogen bond network and stacking forces between the polysaccharide chains in cellulose microfibers. In this paper, the fragment molecular orbital (FMO) method at the correlated Møller–Plesset second order perturbation level of theory was used on a model of the crystalline cellulose Iα core with a total of 144 glucose units. These computations show that the intersheet chain interactions are stronger than the intrasheet chain interactions for the crystalline structure, while they are more similar to each other for a relaxed structure. An FMO chain pair interaction energy decomposition analysis for both the crystal and relaxed structures reveals an intricate interplay between electrostatic, dispersion, charge transfer, and exchange repulsion effects. The role of the primary alcohol groups in stabilizing the interchain hydrogen bond network in the inner sheet of the crystal and relaxed structures of cellulose Iα, where edge effects are absent, was analyzed. Finally, the maximum attractive intrasheet interaction is observed for the GT-TG residue pair with one intrasheet hydrogen bond, suggesting that the relative orientation of the residues is as important as the hydrogen bond network in strengthening the interaction between the residues.

37 INORGANIC, ORGANIC, PHYSICAL, AND ANALYTICAL CH↗
DOE OSTI2013

Initial Recognition of a Cellodextrin Chain in the Cellulose-Binding Tunnel May Affect Cellobiohydrolase Directional Specificity

Cellobiohydrolases processively hydrolyze glycosidic linkages in individual polymer chains of cellulose microfibrils, and typically exhibit specificity for either the reducing or nonreducing end of cellulose. Here in this article, we conduct molecular dynamics simulations and free energy calculations to examine the initial binding of a cellulose chain into the catalytic tunnel of the reducing-end-specific Family 7 cellobiohydrolase (Cel7A) from Hypocrea jecorina. In unrestrained simulations, the cellulose diffuses into the tunnel from the -7 to the -5 positions, and the associated free energy profiles exhibit no barriers for initial processivity. The comparison of the free energy profiles for different cellulose chain orientations show a thermodynamic preference for the reducing end, suggesting that the preferential initial binding may affect the directional specificity of the enzyme by impeding nonproductive (nonreducing end) binding. Finally, the Trp-40 at the tunnel entrance is shown with free energy calculations to have a significant effect on initial chain complexation in Cel7A.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2013

Mathematical and Numerical Aspects of the Adaptive Fast Multipole Poisson-Boltzmann Solver

This paper summarizes the mathematical and numerical theories and computational elements of the adaptive fast multipole Poisson-Boltzmann (AFMPB) solver. We introduce and discuss the following components in order: the Poisson-Boltzmann model, boundary integral equation reformulation, surface mesh generation, the nodepatch discretization approach, Krylov iterative methods, the new version of fast multipole methods (FMMs), and a dynamic prioritization technique for scheduling parallel operations. For each component, we also remark on feasible approaches for further improvements in efficiency, accuracy and applicability of the AFMPB solver to large-scale long-time molecular dynamics simulations. Lastly, the potential of the solver is demonstrated with preliminary numerical results.

97 MATHEMATICS AND COMPUTING↗
DOE OSTI2012

REACH coarse-grained simulation of a cellulose fiber

A molecular level understanding of the structure, dynamics and mechanics of cellulose fibers can aid in understanding the recalcitrance of biomass to hydrolysis in cellulosic biofuel production. Here, a residue-scale REACH (Realistic Extension Algorithm via Covariance Hessian) coarse-grained force field was derived from all-atom molecular dynamics (MD) simulations of the crystalline Iβ cellulose fibril. REACH maps the atomistic covariance matrix onto coarse-grained elastic force constants. The REACH force field was found to reproduce the positional fluctuations and low-frequency vibrational spectra from the all-atom model, allowing elastic properties of the cellulose fibril to be characterized using the coarse-grained force field with a speedup of >20 relative to atomistic MD on systems of the same size. The calculated longitudinal/transversal Young s modulus and the velocity of sound are in agreement with experiment. The persistence length of a 36-chain cellulose microcrystal was estimated to be ~380 μm. In conclusion, the normal-mode analysis with the REACH force field suggests that intrinsic dynamics might facilitate the deconstruction of the cellulose fibril from the hydrophobic surface.

59 BASIC BIOLOGICAL SCIENCES↗
DOE OSTI2012

Surface hydration amplifies single-well protein atom diffusion propagating into the macromolecular core

The effect of surface hydration water on internal protein motion is of fundamental interest in molecular biophysics. Here, by decomposing the picosecond to nanosecond atomic motion in molecular dynamics simulations of lysozyme at different hydration levels into three components localized single-well diffusion, methyl group rotation, and nonmethyl jumps we show that the effect of surface hydration is mainly to increase the volume of the localized single-well diffusion. As a result, these diffusive motions are coupled in such a way that the hydration effect propagates from the protein surface into the dry core.

59 BASIC BIOLOGICAL SCIENCES↗
DOE OSTI2012

Interactions between Ether Phospholipids and Cholesterol as Determined by Scattering and Molecular Dynamics Simulations

Cholesterol and ether lipids are ubiquitous in mammalian cell membranes, and their interactions are crucial in ether lipid mediated cholesterol trafficking. We report on cholesterol s molecular interactions with ether lipids as determined using a combination of small-angle neutron and Xray scattering, and all-atom molecular dynamics (MD) simulations. A scattering density profile model for an ether lipid bilayer was developed using MD simulations, which was then used to simultaneously fit the different experimental scattering data. From analysis of the data the various bilayer structural parameters were obtained. Surface area constrained MD simulations were also performed to reproduce the experimental data. This iterative analysis approach resulted in good agreement between the experimental and simulated form factors. The molecular interactions taking place between cholesterol and ether lipids were then determined from the validated MD simulations. We found that in ether membranes cholesterol primarily hydrogen bonds with the lipid headgroup phosphate oxygen, while in their ester membrane counterparts cholesterol hydrogen bonds with the backbone ester carbonyls. This different mode of interaction between ether lipids and cholesterol induces cholesterol to reside closer to the bilayer surface, dehydrating the headgroup s phosphate moiety. Moreover, the three-dimensional lipid chain spatial density distribution around cholesterol indicates anisotropic chain packing, causing cholesterol to tilt. These insights lend a better understanding of ether lipid-mediated cholesterol trafficking and the roles that the different lipid species have in determining the structural and dynamical properties of membrane associated biomolecules.

EQ-SANS↗
DOE OSTI2011

Intramembrane Proton Binding Site Linked to Activation of Bacterial Pentameric Ion Channel

Prokaryotic orthologs of eukaryotic Cys-loop receptor channels recently emerged as structural and mechanistic surrogates to investigate this superfamily of intercellular signaling proteins. Here, we examine proton activation of the prokaryotic ortholog GLIC using patch clamp electrophysiology, mutagenesis, and molecular dynamics (MD) simulations. Whole-cell current recordings from human embryonic kidney (HEK) 293 cells expressing GLIC show half-maximal activation at pH 6, close to the p$K_a$ of histidine, implicating the three native His residues in proton sensing linked to activation. The mutation H235F abolishes proton activation, H277Y is without effect, and all nine mutations of His-127 prevent expression on the cell surface. In the GLIC crystal structure, His-235 on transmembrane (TM) $α$-helix 2, hydrogen bonds to the main chain carbonyl oxygen of Ile-259 on TM α-helix 3. MD simulations show that when His-235 is protonated, the hydrogen bond persists, and the channel remains in the open conformation, whereas when His-235 is deprotonated, the hydrogen bond dissociates, and the channel closes. Mutations of the proximal Tyr-263, which also links TM α-helices 2 and 3 via a hydrogen bond, alter proton sensitivity over a 1.5 pH unit range. MD simulations show that mutations of Tyr-263 alter the hydrogen bonding capacity of His-235. The overall findings show that His-235 in the TM region of GLIC is a novel proton binding site linked to channel activation.

37 INORGANIC, ORGANIC, PHYSICAL, AND ANALYTICAL CH↗