Publications (68)212.04 Total impact
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Article: The p7 Protein of Hepatitis C Virus Forms Structurally Plastic, Minimalist Ion Channels.
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ABSTRACT: Hepatitis C virus (HCV) p7 is a membrane-associated oligomeric protein harboring ion channel activity. It is essential for effective assembly and release of infectious HCV particles and an attractive target for antiviral intervention. Yet, the self-assembly and molecular mechanism of p7 ion channelling are currently only partially understood. Using molecular dynamics simulations (aggregate time 1.2 µs), we show that p7 can form stable oligomers of four to seven subunits, with a bias towards six or seven subunits, and suggest that p7 self-assembles in a sequential manner, with tetrameric and pentameric complexes forming as intermediate states leading to the final hexameric or heptameric assembly. We describe a model of a hexameric p7 complex, which forms a transiently-open channel capable of conducting ions in simulation. We investigate the ability of the hexameric model to flexibly rearrange to adapt to the local lipid environment, and demonstrate how this model can be reconciled with low-resolution electron microscopy data. In the light of these results, a view of p7 oligomerization is proposed, wherein hexameric and heptameric complexes may coexist, forming minimalist, yet robust functional ion channels. In the absence of a high-resolution p7 structure, the models presented in this paper can prove valuable as a substitute structure in future studies of p7 function, or in the search for p7-inhibiting drugs.PLoS Computational Biology 09/2012; 8(9):e1002702. · 5.22 Impact Factor -
Article: Edge effects control helical wrapping of carbon nanotubes by polysaccharides.
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ABSTRACT: Carbon nanotubes (CNTs) wrapped by polysaccharide chains via noncovalent interactions have been shown to be soluble and dispersed in aqueous environments, and have several potential chemical and biomedical applications. The wrapping mechanism, in particular the role played by the end of the CNT, remains, however, unknown. In this work, a hybrid complex formed by an amylose (AMYL) chain and a single-walled carbon nanotube (SWNT) has been examined by means of atomistic molecular dynamics (MD) simulations to assess its propensity toward self-assembly, alongside its structural characteristics in water. To explore edge effects, the middle and end regions of the SWNT have been chosen as two initial wrapping sites, to which two relative orientations have been assigned, i.e. parallel and orthogonal. The present results prove that AMYL can wrap spontaneously around the tubular surface, starting from the end of the SWNT and driven by both favorable van der Waals attraction and hydrophobic interactions, and resulting in a perfectly compact, helical conformation stabilized by an interlaced hydrogen-bond network. Principal component analysis carried out over the MD trajectories reveals that stepwise burial of hydrophobic faces of pyranose rings controlled by hydrophobic interactions is a key step in the formation of the helix. Conversely, if wrapping proceeds from the middle of the SWNT, self-organization into a helical structure is not observed due to strong van der Waals attractions preventing the hydrophobic faces of the AMYL chain generating enough contacts with the tubular surface.Nanoscale 03/2012; 4(8):2584-9. · 5.91 Impact Factor -
Article: The effects of 7-dehydrocholesterol on the structural properties of membranes.
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ABSTRACT: Smith-Lemli-Opitz syndrome, a congenital and developmental malformation disease, is typified by abnormal accumulation of 7-dehydrocholesterol (7DHC), the immediate precursor of cholesterol (CHOL), and depletion thereof. Knowledge of the effect of 7DHC on the biological membrane is, however, still fragmentary. In this study, large-scale atomistic molecular dynamics simulations, employing two distinct force fields, have been conducted to elucidate differences in the structural properties of a hydrated dimyristoylphosphatidylcholine bilayer due to CHOL and 7DHC. The present series of results indicate that CHOL and 7DHC possess virtually the same ability to condense and order membranes. Furthermore, the condensing and ordering effects are shown to be strengthened at increasing sterol concentrations.Physical Biology 08/2011; 8(5):056005. · 2.60 Impact Factor -
Article: Oligomerization state of photosynthetic core complexes is correlated with the dimerization affinity of a transmembrane helix.
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ABSTRACT: In the Rhodobacter (Rba.) species of photosynthetic purple bacteria, a single transmembrane α-helix, PufX, is found within the core complex, an essential photosynthetic macromolecular assembly that performs the absorption and the initial processing of light energy. Despite its structural simplicity, many unresolved questions surround PufX, the most important of which is its location within the photosynthetic core complex. One proposed placement of PufX is at the center of a core complex dimer, where two PufX helices associate in the membrane and form a homodimer. Inability for PufX of certain Rba. species to form a homodimer is thought to lead to monomeric core complexes. In the present study, we employ a combination of computational and experimental techniques to test the hypothesized homodimerization of PufX. We carry out a systematic investigation to measure the dimerization affinity of PufX from four Rba. species, Rba. blasticus , Rba. capsulatus , Rba. sphaeroides , and Rba. veldkampii , using a molecular dynamics-based free-energy method, as well as experimental TOXCAT assays. We found that the four PufX helices have substantially different dimerization affinities. Both computational and experimental techniques demonstrate that species with dimeric core complexes have PufX that can potentially form a homodimer, whereas the one species with monomeric core complexes has a PufX with little to no dimerization propensity. Our analysis of the helix-helix interface revealed a number of positions that may be important for PufX dimerization and the formation of a hydrogen-bond network between these GxxxG-containing helices. Our results suggest that the different oligomerization states of core complexes in various Rba. species can be attributed, among other factors, to the different propensity of its PufX helix to homodimerize.Journal of the American Chemical Society 08/2011; 133(35):14071-81. · 9.91 Impact Factor -
Article: Cytoplasmic domain filter function in the mechanosensitive channel of small conductance.
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ABSTRACT: Mechanosensitive channels, inner membrane proteins of bacteria, open and close in response to mechanical stimuli such as changes in membrane tension during osmotic stress. In bacteria, these channels act as safety valves preventing cell lysis upon hypoosmotic cell swelling: the channels open under membrane tension to release osmolytes along with water. The mechanosensitive channel of small conductance, MscS, consists, in addition to the transmembrane channel, of a large cytoplasmic domain (CD) that features a balloon-like, water filled chamber opening to the cytoplasm through seven side pores and a small distal pore. The CD is apparently a molecular sieve covering the channel that optimizes loss of osmolytes during osmoadaptation. We employ diffusion theory and molecular dynamics simulations to explore the transport kinetics of Glu(-) and K(+) as representative osmolytes. We suggest that the CD indeed acts as a filter that actually balances passage of Glu(-) and K(+), and possibly other positive and negative osmolytes, to yield a largely neutral efflux and, thereby, reduce cell depolarization in the open state and conserve to a large degree the essential metabolite Glu(-).Biophysical Journal 07/2011; 101(1):80-9. · 3.65 Impact Factor -
Article: Free energy of nascent-chain folding in the translocon.
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ABSTRACT: During their synthesis, many water-soluble proteins and nearly all membrane proteins transit through a protein-conducting channel in the membrane, the Sec translocon, from where they are inserted into the lipid bilayer. Increasing evidence indicates that folding of the nascent protein begins already within the ribosomal exit tunnel in a sequence- and environment-dependent fashion. To examine the effects of the translocon on the nascent-chain folding, we have calculated the potential of mean force for α-helix formation of a 10-alanine oligopeptide as a function of its position within the translocon channel. We find that the predominant conformational states, α-helical and extended, reflect those found for the peptide in water. However, the translocon, via its surface properties and its variable diameter, shifts the equilibrium in favor of the α-helical state. Thus, we suggest that the translocon facilitates not only the insertion of membrane proteins into the bilayer but also their folding.Journal of the American Chemical Society 05/2011; 133(19):7602-7. · 9.91 Impact Factor -
Article: Polarization effects in molecular interactions
Wiley Interdisciplinary Reviews: Computational Molecular Science. 02/2011; 1(5):844 - 854. -
Article: Free-energy cost for translocon-assisted insertion of membrane proteins.
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ABSTRACT: Nascent membrane proteins typically insert in a sequential fashion into the membrane via a protein-conducting channel, the Sec translocon. How this process occurs is still unclear, although a thermodynamic partitioning between the channel and the membrane environment has been proposed. Experiment- and simulation-based scales for the insertion free energy of various amino acids are, however, at variance, the former appearing to lie in a narrower range than the latter. Membrane insertion of arginine, for instance, requires 14-17 kcal/mol according to molecular dynamics simulations, but only 2-3 kcal/mol according to experiment. We suggest that this disagreement is resolved by assuming a two-stage insertion process wherein the first step, the insertion into the translocon, is energized by protein synthesis and, therefore, has an effectively zero free-energy cost; the second step, the insertion into the membrane, invokes the translocon as an intermediary between the fully hydrated and the fully inserted locations. Using free-energy perturbation calculations, the effective transfer free energies from the translocon to the membrane have been determined for both arginine and leucine amino acids carried by a background polyleucine helix. Indeed, the insertion penalty for arginine as well as the insertion gain for leucine from the translocon to the membrane is found to be significantly reduced compared to direct insertion from water, resulting in the same compression as observed in the experiment-based scale.Proceedings of the National Academy of Sciences 02/2011; 108(9):3596-601. · 9.68 Impact Factor -
Article: Free-Energy Landscape of the Helical Wrapping of a Carbon Nanotube by a Polysaccharide
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ABSTRACT: Carbon nanotubes wrapped by polysaccharide chains like chitosan (CHTS) or its derivatives through noncovalent decoration have been shown to condense effectively and deliver DNA for gene therapy. Despite the importance of these novel nanoscale materials, the detail of the microscopic structure and underlying interaction mechanism is still fragmentary. In the present work, the complex formed by CHTS and a single-walled carbon nanotube (SWNT) has been investigated by means of atomistic molecular dynamics (MD) simulations to explore its propensity toward self-assembly, together with its structural properties in an aqueous environment. The present results reveal that CHTS can wrap spontaneously the tubular surface by regulating backbone torsional stress upon van der Waals attraction by the SWNT, resulting in a steady, right-handed helical conformation. The free-energy landscape characterizing the wrapping process of the CHTS chain from a straight conformation to a tight helical one brings to light two energetically favored helical conformations corresponding to distinct pitches. In addition, the degree of deacetylation of the polysaccharide chain, but not the pH, induces pronounced fluctuations in the geometrical properties of the helix.01/2011; -
Article: Structural characterization of micelles formed of cholesteryl-functionalized cyclodextrins.
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ABSTRACT: Amphiphilic cholesteryl 2,6-di-O-methyl-β-cyclodextrins (chol-DIMEB) can self-aggregate into spherical micelles of noteworthy potential for drug delivery. All-atom molecular dynamics simulations of chol-DIMEB micelles consisting of 3-24 monomers have been performed in aqueous solution. chol-DIMEB exhibits a pronounced tendency to self-assemble into core-shell structures. van der Waals interactions within the cholesteryl nucleus constitute the main driving force responsible for the formation of the micelle. The calculated radii of the hydrophobic core and of the hydrophilic shell for the micellar structure formed by 24 monomers agree well with the experiment. The cyclodextrin moieties are found to be exposed toward the aqueous medium and possess the appropriate flexibility to capture drugs in an effective fashion. Analysis of the solvent accessible surface area and hydration number indicates that the micelles are highly hydrosoluble species and can, therefore, enhance significantly the aqueous solubility of lipophilic drugs. In addition, the spatial structure of the micelles is suggestive of multiple potential drug binding sites. The present contribution unveils how micelles endowed with specific characteristics can form, while opening exciting perspectives for the design of novel micellar nanoparticles envisioned to be drug carriers of high potential.Langmuir 01/2011; 27(1):91-7. · 4.19 Impact Factor -
Article: Solubilities inferred from the combination of experiment and simulation. Case study of quercetin in a variety of solvents.
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ABSTRACT: A strategy to infer solubilities from the combination of experiment and all-atom simulations is presented. From a single experimental estimate, the solubility of a substrate can be predicted in various environments from the related free energies of solvation. In the case of quercetin, the methodology was shown to reproduce the experimental solubilities in chloroform, water, acetonitrile, acetone, and tert-amyl alcohol within 0.5 log unit. The reliability of the estimates is markedly correlated to the accuracy of the experimental measure and to both the accuracy and precision of the computed free energies of solvation.The Journal of Physical Chemistry B 09/2010; 114(38):12308-13. · 3.70 Impact Factor -
Article: Good practices in free-energy calculations.
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ABSTRACT: As access to computational resources continues to increase, free-energy calculations have emerged as a powerful tool that can play a predictive role in a wide range of research areas. Yet, the reliability of these calculations can often be improved significantly if a number of precepts, or good practices, are followed. Although the theory upon which these good practices rely has largely been known for many years, it is often overlooked or simply ignored. In other cases, the theoretical developments are too recent for their potential to be fully grasped and merged into popular platforms for the computation of free-energy differences. In this contribution, the current best practices for carrying out free-energy calculations using free energy perturbation and nonequilibrium work methods are discussed, demonstrating that at little to no additional cost, free-energy estimates could be markedly improved and bounded by meaningful error estimates. Monitoring the probability distributions that underlie the transformation between the states of interest, performing the calculation bidirectionally, stratifying the reaction pathway, and choosing the most appropriate paradigms and algorithms for transforming between states offer significant gains in both accuracy and precision.The Journal of Physical Chemistry B 08/2010; 114(32):10235-53. · 3.70 Impact Factor -
Article: Insights into the Recognition and Association of Transmembrane alpha-Helices. The Free Energy of alpha-Helix Dimerization in Glycophorin A.
Journal of the American Chemical Society 06/2010; · 9.91 Impact Factor -
Article: Solubilizing carbon nanotubes through noncovalent functionalization. Insight from the reversible wrapping of alginic acid around a single-walled carbon nanotube.
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ABSTRACT: Carbon nanotubes coated with alginic acid (AA) through noncovalent functionalization have been shown to be soluble and dispersed in water. In the present contribution, all-atom molecular dynamics simulations have been performed to probe the self-assembly mechanism that underlies the formation of complexes by AA and a single-walled carbon nanotube (SWCNT), both in the gas phase and in an aqueous solution. Results of these simulations reveal that AA can wrap around SWCNT by virtue of van der Waals attractions and organize into a compact helical structure, a process induced in the gas phase by hydrogen-bonding interactions. In contrast, in an alginate aqueous solution, a loose helical wrapping mode is found to be favored by virtue of electrostatic repulsions in conjunction with the weakening of hydrogen-bonding interactions. Documented experimentally (Liu, Y.; et al. Small 2006, 2, 874-878) and coined "Great Wall of China" motif, the typical arrangement of AA residues around the tubular structure, conducive to dissolve nanotubes, is observed in the present simulations. Investigation of metal cations binding to AA suggests that calcium ions can mediate aggregation of AA chains by interacting strongly with the carboxylate groups, thereby leading to reverse unwrapping. The results reported in this work shed meaningful light on the potential of noncovalent functionalization for solubilizing carbon nanotubes, and open exciting perspectives for the design of new wrapping agents that are envisioned to form the basis of innovative nanomaterials targeted at chemical and biomedical applications.The Journal of Physical Chemistry B 03/2010; 114(17):5783-9. · 3.70 Impact Factor -
Article: Exploring Multidimensional Free Energy Landscapes Using Time-Dependent Biases on Collective Variables
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ABSTRACT: A new implementation of the adaptive biasing force (ABF) method is described. This implementation supports a wide range of collective variables and can be applied to the computation of multidimensional energy profiles. It is provided to the community as part of a code that implements several analogous methods, including metadynamics. ABF and metadynamics have not previously been tested side by side on identical systems. Here, numerical tests are carried out on processes including conformational changes in model peptides and translocation of a halide ion across a lipid membrane through a peptide nanotube. On the basis of these examples, we discuss similarities and differences between the ABF and metadynamics schemes. Both approaches provide enhanced sampling and free energy profiles in quantitative agreement with each other in different applications. The method of choice depends on the dimension of the reaction coordinate space, the height of the barriers, and the relaxation times of degrees of freedom in the orthogonal space, which are not explicitly described by the chosen collective variables.12/2009; -
Article: Membrane curvature induced by aggregates of LH2s and monomeric LH1s.
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ABSTRACT: The photosynthetic apparatus of purple bacteria is contained within organelles called chromatophores, which form as extensions of the cytoplasmic membrane. The shape of these chromatophores can be spherical (as in Rhodobacter sphaeroides), lamellar (as in Rhodopseudomonas acidophila and Phaeospirillum molischianum), or tubular (as in certain Rb. sphaeroides mutants). Chromatophore shape is thought to be influenced by the integral membrane proteins Light Harvesting Complexes I and II (LH1 and LH2), which pack tightly together in the chromatophore. It has been suggested that the shape of LH2, together with its close packing in the membrane, induces membrane curvature. The mechanism of LH2-induced curvature is explored via molecular dynamics simulations of multiple LH2 complexes in a membrane patch. LH2s from three species-Rb. sphaeroides, Rps. acidophila, and Phsp. molischianum-were simulated in different packing arrangements. In each case, the LH2s pack together and tilt with respect to neighboring LH2s in a way that produces an overall curvature. This curvature appears to be driven by a combination of LH2's shape and electrostatic forces that are modulated by the presence of well-conserved cytoplasmic charged residues, the removal of which inhibits LH2 curvature. The interaction of LH2s and an LH1 monomer is also explored, and it suggests that curvature is diminished by the presence of LH1 monomers. The implications of our results for chromatophore shape are discussed.Biophysical Journal 12/2009; 97(11):2978-84. · 3.65 Impact Factor -
Article: A glycophorin A-like framework for the dimerization of photosynthetic core complexes.
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ABSTRACT: The core complex in photosynthetic bacteria plays a central role in photosynthesis. This molecular assembly is composed of two protein complexes, viz., the light-harvesting complex I (LH1), which absorbs sunlight by means of the protein-bound bacteriochlorophylls, and the reaction center (RC), which uses the light-excitation energy absorbed by the LH complexes to produce a transmembrane (TM) charge gradient, subsequently employed for energy conversion. In Rhodobacter (Rba.) sphaeroides, the core complex contains, in addition, two copies of the single TM alpha-helix protein, PufX, and forms a (RC-LH1-PufX)(2) dimer. To this date, no high-resolution structure has been reported for the entire core complex. In particular, the location of PufX within the (RC-LH1-PufX)(2) dimer is still the subject of much debate. Here, one of the proposed locations for PufX, requiring its dimerization, is examined. The PufX-dimer model on the basis of the glycophorin A (GpA) dimer was constructed, and its robustness was probed through a series of molecular dynamics (MD) simulations. The free-energy change due to the replacement of Gly35 by valine was also determined to assess whether this mutation is responsible for distinct PufX oligomerization states in different Rba. species. The present study shows that PufX helices form a stable GpA-like dimer with a helix-helix crossing angle that could constitute the molecular basis of the reported highly bent and V-shaped structure of the Rba. sphaeroides core complex dimer.Journal of the American Chemical Society 11/2009; 131(47):17096-8. · 9.91 Impact Factor -
Article: High-chloride concentrations abolish the binding of adenine nucleotides in the mitochondrial ADP/ATP carrier family.
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ABSTRACT: The ADP/ATP carrier (AAC) is a very effective membrane protein that mediates the exchange of ADP and ATP across the mitochondrial membrane. In vivo transport measurements on the AAC overexpressed in Escherichia coli demonstrate that this process can be severely inhibited by high-chloride concentrations. Molecular-dynamics simulations reveal a strong modification of the topology of the local electric field related to the number of chloride ions inside the cavity. Halide ions are shown to shield the positive charges lining the internal cavity of the carrier by accurate targeting of key basic residues. These specific amino acids are highly conserved as highlighted by the analysis of multiple AAC sequences. These results strongly suggest that the chloride concentration acts as an electrostatic lock for the mitochondrial AAC family, thereby preventing adenine nucleotides from reaching their dedicated binding sites.Biophysical Journal 11/2009; 97(10):L25-7. · 3.65 Impact Factor -
Article: Inclusion mechanism of steroid drugs into beta-cyclodextrins. Insights from free energy calculations.
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ABSTRACT: The inclusion of hydrocortisone, progesterone, and testosterone into the cavity of beta-cyclodextrin (beta-CD) following two possible orientations was investigated using molecular dynamics simulations and free-energy calculations. The free-energy profiles that delineate the inclusion process were determined using an adaptive biasing force. The present results reveal that although the free-energy surfaces feature two local minima corresponding to a partial and a complete inclusion, the former mode is markedly preferred, irrespective of the orientation. Ranking the propensity of the three steroidal molecules to associate with beta-CD, viz. progesterone>testosterone>hydrocortisone, is shown to be in excellent agreement with experiment. This conclusion is further supported by independent calculations relying on alchemical transformations in conjunction with free energy perturbation, wherein the relative binding free energy for the three steroids was estimated. In addition, decomposition of the potentials of mean force into free-energy contributions and significant decrease in the total hydrophobic surface area suggest that by and large, van der Waals and hydrophobic interactions constitute the main driving forces responsible for the formation of the inclusion complexes. Analysis of their structural features from the molecular dynamics trajectories brings to light different hydrogen-bonding patterns that are characterized by distinct dynamics and stabilities.The Journal of Physical Chemistry B 05/2009; 113(22):7836-43. · 3.70 Impact Factor -
Article: Polarizable intermolecular potentials for water and benzene interacting with halide and metal ions.
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ABSTRACT: A complete derivation of polarizable intermolecular potentials based on high-level, gas-phase quantum-mechanical calculations is proposed. The importance of appreciable accuracy together with inherent simplicity represents a significant endeavor when enhancement of existing force fields for biological systems is sought. Toward this end, symmetry-adapted perturbation theory (SAPT) can provide an expansion of the total interaction energy into physically meaningful e.g. electrostatic, induction and van der Waals terms. Each contribution can be readily compared with its counterpart in classical force fields. Since the complexity of the different intermolecular terms cannot be fully embraced using a minimalist description, it is necessary to resort to polyvalent expressions capable of encapsulating overlooked contributions from the quantum-mechanical expansion. This choice results in consistent force field components that reflect the underlying physical principles of the phenomena. This simplified potential energy function is detailed and definitive guidelines are drawn. As a proof of concept, the methodology is illustrated through a series of test cases that include the interaction of water and benzene with halide and metal ions. In each case considered, the total energy is reproduced accurately over a range of biologically relevant distances.Journal of Chemical Theory and Computation 01/2009; 5(11):3022-3031. · 5.22 Impact Factor
Top co-authors
Top Journals
Institutions
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2008–2012
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Nankai University
- • College of Chemistry
- • Department of Chemistry
Tianjin, Tianjin Shi, China -
Université Joseph Fourier - Grenoble 1
Grenoble, Rhone-Alpes, France
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2006–2012
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University of Illinois, Urbana-Champaign
- Department of Physics
Urbana, IL, USA -
University of Science and Technology of China
- Department of Chemistry
Hefei, Anhui Sheng, China
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2004–2009
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French National Centre for Scientific Research
Lyon, Rhone-Alpes, France
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1996
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CSU Mentor
Long Beach, CA, USA
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