Louis A. Clark

Franciscan University of Steubenville

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Co-Authors

Randall Q. Snurr

Northwestern University

Herman van Vlijmen

Janssen (Belgium)

Joachim Sauer

Humboldt-Universität zu Berlin

Xianzhi Fu

Fuzhou University

Marek Sierka

Friedrich Schiller University Jena

Shaji Chempath

Clarkson University

Marc A. Anderson

IMDEA Energy Institute

Amit Gupta

Indian Institute of Technology Delhi

George T. Ye

Northwestern University

Matthew Jarpe

Acetylon Pharmaceuticals (United States)

Cooperative Institutions

Biogen (United States)

Northwestern University

University of California, Berkeley

Massachusetts Institute of Technology

University of California, San Francisco

Franciscan University of Steubenville

Biogen (Switzerland)

Stony Brook University

University of Wisconsin–Madison

Los Alamos National Laboratory

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Influence of denatured and intermediate states of folding on protein aggregation

Protein Science (2005)

Nicolas L. Fawzi Victor Chubukov Louis A. Clark Scott P. Brown Teresa Head‐Gordon

We simulate the aggregation thermodynamics and kinetics of proteins L and G, each of which self-assembles to the same alpha/beta [corrected] topology through distinct folding mechanisms. We find that the aggregation kinetics of both proteins at an experimentally relevant concentration exhibit both fast and slow aggregation pathways, although a greater proportion of protein G aggregation events are slow relative to those of found for protein L. These kinetic differences are correlated with the amount and distribution of intrachain contacts formed in the denatured state ensemble (DSE), or an intermediate state ensemble (ISE) if it exists, as well as the folding timescales of the two proteins. Protein G aggregates more slowly than protein L due to its rapidly formed folding intermediate, which exhibits native intrachain contacts spread across the protein, suggesting that certain early folding intermediates may be selected for by evolution due to their protective role against unwanted aggregation. Protein L shows only localized native structure in the DSE with timescales of folding that are commensurate with the aggregation timescale, leaving it vulnerable to domain swapping or nonnative interactions with other chains that increase the aggregation rate. Folding experiments that characterize the structural signatures of the DSE, ISE, or the transition state ensemble (TSE) under nonaggregating conditions should be able to predict regions where interchain contacts will be made in the aggregate, and to predict slower aggregation rates for proteins with contacts that are dispersed across the fold. Since proteins L and G can both form amyloid fibrils, this work also provides mechanistic and structural insight into the formation of prefibrillar species.

Folding (DSP implementation)

10.1110/ps.041177505

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Citations (50)

Characterization of Acidic OH Groups in Zeolites of Different Types: An Interpretation of NH₃-TPD Results in the Light of Confinement Effects

The Journal of Physical Chemistry B (2002)

B. Hunger Matthias Heuchel Louis A. Clark Randall Q. Snurr

Ammonia TPD experiments have been carried out on protonated forms of the zeolites FAU, FER, MFI, and MOR to investigate the acid strength dependence on OH group location and Al content. Effective adsorption energy distributions are derived using a regularization method and corrected to achieve a truer measure of acid strength using nonspecific interaction energies from atomistic Monte Carlo simulations. The correction energies include all interactions not associated with the OH groups and range from 18 to 37 kJ/mol, depending on the region and the zeolite structure. In the FAU structure, we find a bimodal distribution of adsorption energies in both the supercages and the sodalite cages, with the stronger acid sites being more common in the supercages. In contrast, essentially the same acid strength for different regions in MOR is seen, though the acid strength for those sites in the side pockets may be slightly lower. For FER and MFI, the TPD gives unimodal distributions and therefore prohibits distinction between different regions. In agreement with the model of Barthomeuf et al., we see an apparently linear decline (60 kJ/mol) in acid strength beyond a certain aluminum framework density. However, we see a smaller but consistent increase (16 kJ/mol) in acidity before this threshold, despite model predictions that it should be constant.

Sodalite

Acid strength

10.1021/jp012688n

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Citations (93)

Stable Mechanistically-Relevant Aromatic-Based Carbenium Ions in Zeolite Catalysts

Journal of the American Chemical Society (2003)

Louis A. Clark Marek Sierka Joachim Sauer

The existence of carbenium ion species is assumed in many zeolite catalysis mechanisms. Using computational techniques that include environmental effects, a benzenium-type carbenium ion is identified in zeolite catalysts for the first time. Localization of nearby transition states indicate that this species may play an important role as an intermediate in the bimolecular m-xylene disproportionation reaction. The barrier to back-donation of the proton from the benzenium ion is at least 50 kJ/mol, meaning that this species may be spectroscopically observable. An additional carbenium ion intermediate, formed by abstraction of a hydride from m-xylene, is also predicted. The stability of this second new carbenium ion suggests that aromatic-based carbenium ions are likely to be intermediates in many zeolite-catalyzed reactions. Two types of fundamentally different fully periodic calculations support the stability predictions.

Carbenium ion

10.1021/ja0283302

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Citations (96)

Trends in Antibody Sequence Changes during the Somatic Hypermutation Process

The Journal of Immunology (2006)

Louis A. Clark Skanth Ganesan Sarah Papp Herman van Vlijmen

Abstract Probable germline gene sequences from thousands of aligned mature Ab sequences are inferred using simple computational matching to known V(D)J genes. Comparison of the germline to mature sequences in a structural region-dependent fashion allows insights into the methods that nature uses to mature Abs during the somatic hypermutation process. Four factors determine the residue type mutation patterns: biases in the germline, accessibility from single base permutations, location of mutation hotspots, and functional pressures during selection. Germline repertoires at positions that commonly contact the Ag are biased with tyrosine, serine, and tryptophan. These residue types have a high tendency to be present in mutation hotspot motifs, and their abundance is decreased during maturation by a net conversion to other types. The heavy use of tyrosines on mature Ab interfaces is thus a reflection of the germline composition rather than being due to selection during maturation. Potentially stabilizing changes such as increased proline usage and a small number of double cysteine mutations capable of forming disulfide bonds are ascribed to somatic hypermutation. Histidine is the only residue type for which usage increases in each of the interface, core, and surface regions. The net overall effect is a conversion from residue types that could provide nonspecific initial binding into a diversity of types that improve affinity and stability. Average mutation probabilities are ∼4% for core residues, ∼5% for surface residues, and ∼12% for residues in common Ag-contacting positions, excepting the those coded by the D gene.

Gene conversion

10.4049/jimmunol.177.1.333

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Citations (87)

Field trials of a TiO₂pellet‐based photocatalytic reactor for off‐gas treatment at a soil vapor extraction well

Journal of Soil Contamination (1996)

Harry W. Read Xianzhi Fu Louis A. Clark Marc A. Anderson T.R. Jarosch

Abstract A field trial of a pilot‐scale TiO2 photocatalytic reactor for treatment of off‐gases from a soil vapor extraction (SVE) well at a chlorinated solvent spill site at the Savannah River Site near Aiken, SC, is described. Trichloroethylene (TCE), perchloroethylene (PCE), 1,1‐dichloroethylene (1,1 ‐DCE), and 1,1,1 ‐trichloroethane (1,1,1 ‐TCA) were treated at flow rates up to 6 1/min and space times of 5.1 x 107 to 1.2 x 109 g/mol. The TiO2 used was in the form of porous pellets with a surface area of 150 m2/g. Operation of the reactor with the undiluted waste stream (5000 ppmv) at 80, 100, and 110°C yielded many undesirable byproducts, such as phosgene, chloroform, carbon tetrachloride, and penta‐ and hexachloroethane, even though the conversion of PCE and TCE approached 100%. After diluting the waste stream with ambient air to below 1000 ppmv and maintaining space times around 5 x 108 g/mol, a conversion >99.5% was achieved with the production of only small amounts (<10 ppmv) of hexachloroethane. The reactor was Operated continuously for 8 d, with no noticeable deterioration in catalyst activity. In a subsequent laboratory study to determine the mass balance, CO2 determined in the reactor effluent accounted for 80% of the influent carbon. Key words: gas‐phase photocatalysistitanium dioxideperchloroethylenesoil vapor extractionsoil remediation.

Soil vapor extraction

Tetrachloroethylene

Savannah River Site

10.1080/15320389609383522

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Citations (16)

Object-oriented Programming Paradigms for Molecular Modeling

Molecular Simulation (2003)

Amit Gupta Shaji Chempath Martin J. Sanborn Louis A. Clark Randall Q. Snurr

This paper discusses the application of object-oriented programming (OOP) design concepts to the development of molecular simulation code. A number of new languages such as Fortran 90 (F90) have been developed over the last decade that support the OOP design philosophy. We briefly describe the salient features of F90 and some basic object-oriented design principles. As an illustration of the design concepts we implement a general interface in F90 for calculating pairwise interactions that can be extended easily to any number of different forcefield models. The ideas presented here are used in the development of a mu ltipurpose si mulation c ode, named Music. An example of the use of Music for grand canonical Monte Carlo (GCMC) simulations of flexible sorbate molecules in zeolites is given. The example illustrates how OOP allowed existing code for molecular dynamics and GCMC to be easily combined to perform hybrid GCMC simulations with minimal coding effort.

Fortran

Ode

10.1080/0892702031000065719

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Citations (371)

Diffusion mechanisms of normal alkanes in faujasite zeolites

The Journal of Chemical Physics (1999)

Louis A. Clark George T. Ye Amit Gupta Linda L. Hall Randall Q. Snurr

Molecular dynamics simulations of C1 through C14 n-alkanes in a siliceous faujasite zeolite are used to elucidate diffusion mechanisms. Additional simulations of the bulk liquids are conducted to compare the liquid and adsorbed phases. Heats of adsorption, diffusivities, and activation energies are compared with experimental values and agree well. Particularly good agreement is found between predicted self-diffusivities and those measured with pulsed field gradient nuclear magnetic resonance (NMR). Analysis of the chain conformations and motional frequencies indicates that the liquid and adsorbed phases are quite similar, most likely due to the open nature of the faujasite structure. Insights into the influence of local environment on molecular relaxation are also given. Siting results reveal an interesting progression of adsorption sites as the chain length is increased. Shifts of preferred adsorption sites are due to matching between the length scales of sorbate and adsorbent. Alkanes below C6 adsorb preferentially above the 4-rings and 6-rings inside the supercages. For longer chains, the preferred sites shift more toward the center of the supercages. For C8 and above, the molecules spend much of their time in the window regions. These window sites are separated from the supercage sites by unexpected orientational barriers. Consequently, diffusion of longer alkanes in faujasite type structures is not characterized by simple supercage-to-supercage hopping but by hopping between supercage and window sites.

Faujasite

Molecular diffusion

10.1063/1.479306

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Citations (42)

Two general methods for grand canonical ensemble simulation of molecules with internal flexibility

The Journal of Chemical Physics (2003)

Shaji Chempath Louis A. Clark Randall Q. Snurr

Two simulation methods are presented for generating a grand canonical ensemble of molecules with internal degrees of freedom. Molecular dynamics integration is used as a Monte Carlo perturbation move in these methods. The integration move helps to explore the intramolecular degrees of freedom with high acceptance ratios. The proofs of the acceptance criteria for both methods are presented. Tests are described to show that the simulation produces results matching an analytical solution for a simple test system. The method is further tested by predicting adsorption isotherms of n-butane in the zeolite silicalite. An example using these algorithms to generate adsorption isotherms of more complex chiral molecules in chiral zeolitelike materials is also presented.

Grand canonical ensemble

Butane

10.1063/1.1562607

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Citations (42)

Simulated Adsorption Properties and Synthesis Prospects of Homochiral Porous Solids Based on Their Heterochiral Analogs

Langmuir (2004)

Louis A. Clark Shaji Chempath Randall Q. Snurr

Molecular simulations of chiral molecules in porous heterochiral materials were performed to investigate fundamental adsorption properties and possibilities for production of homochiral porous solids. Zeolite BEA polymorph A and zeotype UCSB-7K each provide separated pores of opposite chirality. Single enantiomer and racemic mixture adsorption results are presented and indicate that significant equilibrium enantiomeric excesses of 40-70% in UCSB-7K and 10% in BEA can be achieved. Larger, better-fitting molecules display higher enantiomeric excesses. For dimethylallene, which moves on molecular dynamics time scales in UCSB-7K, self-diffusivities vary by almost an order of magnitude between the two opposite-handed UCSB-7K pores for a given enantiomer. The predicted properties indicate that equilibrium and nonequilibrium strategies using related homochiral materials for separations may be successful. To this end, a discussion of strategies for selectively blocking pores of one chirality on the basis of enantiomer segregation is provided.

Chirality

10.1021/la047722e

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Citations (28)

Protein aggregation determinants from a simplified model: Cooperative folders resist aggregation

Protein Science (2005)

Louis A. Clark

Two-chain aggregation simulations using minimalist models of proteins G, L, and mutants were used to investigate the fundamentals of protein aggregation. Mutations were selected to break up repeats of hydrophobic beads in the sequence while maintaining native topology and folding ability. Data are collected under conditions in which all chain types have similar folded populations and after equilibrating the separated chains to minimize competition between folding and aggregation. Folding cooperativity stands out as the best single-chain determinant under these conditions and for these simple models. It can be experimentally measured by the width of the unfolding transition during thermal denaturation and loosely related to population of intermediate-like states during folding. Additional measures of cooperativity and other properties such as radius of gyration fluctuations and patterning of hydrophobic residues are also examined. Initial contact system states with transition-state characteristics can be identified and are more expanded than average initial contact states. Two-chain minimalist model aggregates are considerably less structured than their native states and have minimal domain-swapping features.

Cooperativity

Folding (DSP implementation)

Radius of gyration

Chain (unit)

Contact order

Denaturation (fissile materials)

10.1110/ps.041017305

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Citations (24)