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Research Interests: Chemistry, Crystallography, Molecular Dynamics Simulation, Biology, Small Angle X Ray Scattering, and 15 moreDNA replication, Medicine, Monte Carlo Simulations, Biological Sciences, Mathematical Sciences, Proteins, Monomer, Solutions, Helicase, Protein Conformation, Dimer, Amino Acid Sequence, Small Angle Neutron Scattering, DNA Helicase, and Molecular Sequence Data
Research Interests: Engineering, Chemistry, Water, Small angle X-ray and neutron scattering, Medicine, and 14 moreLysozyme, Physical sciences, Phase transition, Proteins, Ice, CHEMICAL SCIENCES, Scattering, CARBOHYDRATES, Neutron Scattering, Powders, Small Angle Neutron Scattering, Aqueous Solution, Factor structure, and Monte Carlo Method
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Research Interests: Computer Science, Small angle X-ray and neutron scattering, Small Angle X Ray Scattering, Statistical Physics, Mathematical Sciences, and 10 moreComputer Model, Physical sciences, Protein structure, Macromolecule, Scattering, Neutron Scattering, Small Angle Neutron Scattering, Experimental Data, dihedral angle, and Computer Physics
Research Interests: Biophysics, Chemistry, Molecular Dynamics Simulation, Small angle X-ray and neutron scattering, Neutron Diffraction, and 8 moreMedicine, Molecular modeling, Circular Dichroism, X ray diffraction, THEORETICAL AND COMPUTATIONAL CHEMISTRY, Protein Conformation, Structure activity Relationship, and Monte Carlo Method
Phase transitions of poloxamer 188 (P188) aqueous solutions at freezing temperatures are investigated using small-angle neutron scattering (SANS) and small- and wide-angle X-ray scatterings (SAXS and WAXS). It is shown that P188 solution... more
Phase transitions of poloxamer 188 (P188) aqueous solutions at freezing temperatures are investigated using small-angle neutron scattering (SANS) and small- and wide-angle X-ray scatterings (SAXS and WAXS). It is shown that P188 solution (10%) undergoes the following sequence of phase transitions during cooling from 25 to -150 °C: micelle solution, solution of monomers, two-phase mixture of liquid crystalline mesophase + ice, and finally crystalline P188 + ice. Formation of the liquid crystalline phase during freezing is likely to be triggered by water freezing to ice and corresponding freeze concentration of the remaining solution. During heating of the frozen solutions, the sequence of the phase transitions is reversed: crystalline P188 + ice, liquid crystalline mesophase + ice, monomer solution + ice, monomer solution, and finally micelle solution. Similar phase transitions are detected for dilute solutions of P188 (1%) except that micelle formation is not observed at 25 °C, consistent with the literature reported critical micelle concentration (CMC) at this temperature. The present study provides new insight into P188 aqueous solutions at freezing temperatures and has practical implications on the design and development of pharmaceutical formulations.
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Lipid nanodiscs can be used to solubilize functional membrane proteins (MPs) in nativelike environments. Thus, they are promising reagents that have been proven useful to characterize MPs. Both protein and non-protein molecular belts have... more
Lipid nanodiscs can be used to solubilize functional membrane proteins (MPs) in nativelike environments. Thus, they are promising reagents that have been proven useful to characterize MPs. Both protein and non-protein molecular belts have shown promise to maintain the structural integrity of MPs in lipid nanodiscs. Small-angle neutron scattering (SANS) can be used to determine low-resolution structures of proteins in solution, which can be enhanced through the use of contrast variation methods. We present theoretical contrast variation SANS results for protein and styrene-maleic acid copolymer (SMA) belt 1,2-dimyristoyl-sn-glycero-3-phosphorylcholine (DMPC) nanodiscs with and without additional bound or transmembrane proteins. The predicted scattering properties are derived from atomistic molecular dynamics simulations to account for conformational fluctuations, and we determine deuterium-labeling conditions such that SANS intensity profiles only include contributions from the scattering of the MP of interest. We propose strategies to tune the neutron scattering length densities (SLDs) of the SMA and DMPC using selective deuterium labeling such that the SLD of the nanodisc becomes homogeneous and its scattering can essentially be eliminated in solvents containing an appropriate amount of D2O. These finely tuned labeled polymer-based nanodiscs are expected to be useful to extract the size and molecular shape information of MPs using SANS-based contrast variation experiments, and they can be used with MPs of any molecular weight.
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Research Interests: Engineering, Materials Science, Chemistry, Molecular Dynamics Simulation, Neutron Diffraction, and 15 moreMedicine, Molecular Dynamics, Biological Sciences, Humans, Monoclonal Antibodies, CHEMICAL SCIENCES, Buffers, Analytical and Bioanalytical Chemistry, Neutron Scattering, Freezing, Colloid, Monte Carlo Method, Histidine, immunoglobulin G, and Immunoglobulin Fc Fragments
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Research Interests: Biophysics, Biology, Cell Biology, Medicine, Biological Sciences, and 15 moreCercopithecus aethiops, Mutation, Animals, Endoplasmic Reticulum, Proteins, Solubility, Receptor, Alanine, Golgi Apparatus, Protein Binding, Histidine, Gene Expression Regulation, Titrimetry, protonation, and Medical and Health Sciences
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In the past decade, there was increased research interest in studying internal motions of flexible proteins in solution using Neutron Spin Echo (NSE) as NSE can simultaneously probe the dynamics at the length and time scales comparable to... more
In the past decade, there was increased research interest in studying internal motions of flexible proteins in solution using Neutron Spin Echo (NSE) as NSE can simultaneously probe the dynamics at the length and time scales comparable to protein domain motions. However, the collective intermediate scattering function (ISF) measured by NSE has the contributions from translational, rotational, and internal motions, which are rather complicated to be separated. Widely used NSE theories to interpret experimental data usually assume that the translational and rotational motions of a rigid particle are decoupled and independent to each other. To evaluate the accuracy of this approximation for monoclonal antibody (mAb) proteins in solution, dissipative particle dynamic computer simulation is used here to simulate a rigid-body mAb for up to about 200 ns. The total ISF together with the ISFs due to only the translational and rotational motions as well as their corresponding effective diffus...
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Many biomolecular complexes exist in a flexible ensemble of states in solution which are necessary to perform their biological function. Small angle scattering (SAS) measurements are a popular method for characterizing these flexible... more
Many biomolecular complexes exist in a flexible ensemble of states in solution which are necessary to perform their biological function. Small angle scattering (SAS) measurements are a popular method for characterizing these flexible molecules due to their relative ease of use and ability to simultaneously probe the full ensemble of states. However, SAS data is typically low-dimensional and difficult to interpret without the assistance of additional structural models. In theory, experimental SAS curves can be reconstituted from a linear combination of theoretical models, although this procedure carries significant risk of overfitting the inherently low-dimensional SAS data. Previously, we developed a Bayesian-based method for fitting ensembles of model structures to experimental SAS data that rigorously avoids overfitting. However, we have found that these methods can be difficult to incorporate into typical SAS modeling workflows, especially for users that are not experts in comput...
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The scattering of neutrons can be used to provide information on the structure and dynamics of biological systems on multiple length and time scales. Pursuant to a National Science Foundation-funded workshop in February 2018, recent... more
The scattering of neutrons can be used to provide information on the structure and dynamics of biological systems on multiple length and time scales. Pursuant to a National Science Foundation-funded workshop in February 2018, recent developments in this field are reviewed here, as well as future prospects that can be expected given recent advances in sources, instrumentation and computational power and methods. Crystallography, solution scattering, dynamics, membranes, labeling and imaging are examined. For the extraction of maximum information, the incorporation of judicious specific deuterium labeling, the integration of several types of experiment, and interpretation using high-performance computer simulation models are often found to be particularly powerful.
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Research Interests: Engineering, Mathematics, Algorithms, Medicine, Computer Simulation, and 15 moreFeasibility Studies, Physical sciences, Magnetic Resonance, Terpenes, Laplace Transform, Image Enhancement, Solutions, Magnetic, Chemical Shift, Spectral Estimation, Quinine, Inverse, Inverse Laplace transform, Resolvent, and Diffusion magnetic resonance imaging
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Research Interests: Engineering, Mathematics, Algorithms, Medicine, Computer Simulation, and 13 moreFeasibility Studies, Physical sciences, Magnetic Resonance, Terpenes, Image Enhancement, Solutions, Magnetic, Chemical Shift, Spectral Estimation, Quinine, Inverse Laplace transform, Resolvent, and Diffusion magnetic resonance imaging
ABSTRACTWe present results from studies of the structure and dynamics of clathrate hydrates of three cyclic ethers by neutron diffraction and preliminary results on molecular dynamics simulations. Recent results from neutron powder... more
ABSTRACTWe present results from studies of the structure and dynamics of clathrate hydrates of three cyclic ethers by neutron diffraction and preliminary results on molecular dynamics simulations. Recent results from neutron powder diffraction and quasielastic neutron scattering of studies of propylene oxide (PO, C3H6O) and its isomer trimethyelene oxide (TMO, C3H6O), are compared with structural results obtained previously for tetrahydrofuran (THF, C3H5O). Experimental evidence of distortions of the host structures with temperature is discussed in light of the findings from quasielastic neutron scattering, which indicate distinct regions of high-temperature and low-temperature rotational dynamics and a temperature dependence related to the size of the guest. Preliminary MD results indicate a general expansion of the lattice with temperature resulting in increased volume available to PO.
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Research Interests: Engineering, Chemistry, Protein Folding, Neutron Diffraction, Medicine, and 15 moreMathematical Sciences, Animals, Physical sciences, Phase transition, Proteins, Ice, CHEMICAL SCIENCES, Cattle, Pressure, CARBOHYDRATES, Neutron Scattering, Molecular weight, Powders, Bovine Serum Albumin, and Protein Denaturation
In this study, we used sodium chloride (NaCl) to extensively modulate non-specific protein-protein interactions (PPI) of a humanized anti-streptavidin monoclonal antibody class 2 molecule (ASA-IgG2). The changes in PPI with varying NaCl... more
In this study, we used sodium chloride (NaCl) to extensively modulate non-specific protein-protein interactions (PPI) of a humanized anti-streptavidin monoclonal antibody class 2 molecule (ASA-IgG2). The changes in PPI with varying NaCl (CNaCl) and monoclonal antibody (mAb) concentration (CmAb) were assessed using the diffusion interaction parameter kD and second virial coefficient B22 measured from solutions with low to moderate CmAb. The effective structure factor S(q)eff measured from concentrated mAb solutions using small-angle X-ray and neutron scattering (SAXS/SANS) was also used to characterize the PPI. Our results found that the nature of net PPI changed not only with CNaCl, but also with increasing CmAb. As a result, parameters measured from dilute and concentrated mAb samples could lead to different predictions on the stability of mAb formulations. We also compared experimentally determined viscosity results with those predicted from interaction parameters, including kD an...
Research Interests: Medicine and Antibodies
—Proteins and nucleic acids participate in essentially every biochemical process in living organisms, and the elucidation of their structure and motions is essential for our understanding how these molecular machines perform their... more
—Proteins and nucleic acids participate in essentially every biochemical process in living organisms, and the elucidation of their structure and motions is essential for our understanding how these molecular machines perform their function. Nuclear Magnetic Resonance (NMR) spectroscopy is a powerful versatile technique that provides critical information on the molecular structure and dynamics. Spin-relaxation data are used to determine the overall rotational diffusion and local motions of biological macromolecules, while residual dipolar couplings (RDCs) reveal local and long-range structural architecture of these molecules and their complexes. This information allows researchers to refine structures of proteins and nucleic acids and provides restraints for molecular docking. Several software packages have been developed by NMR researchers in order to tackle the complicated experimental data analysis and structure modeling. However, many of them are offline packages or command-line...
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We present a method, called iRRT, for processing Diffusion Ordered Spectroscopy (DOSY) data, that can produce results even in overlapping regions of the spectrum. From the results we obtain diffusion constants for camphene, geraniol, and... more
We present a method, called iRRT, for processing Diffusion Ordered Spectroscopy (DOSY) data, that can produce results even in overlapping regions of the spectrum. From the results we obtain diffusion constants for camphene, geraniol, and quinine of 12× 10−6cm2s−1, 9× 10−6cm2s−1, and 6× 10−6cm2s−1 respectively. We compare the results from this method to those obtained using a mono-exponential non-linear least squares fit. Both the 2D DOSY spectrum and the 1D spectra corresponding to each component of the mixture obtained from iRRT compare favorably to the spectra of the pure substances, and offer a vast improvement over the exponential fit results. This method is presented as a stable and reliable tool for solving the Inverse Laplace Transform (ILT) problem present in experiments such as DOSY.
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Understanding the structure-function relationship of biomolecules containing DNA has motivated experiments aimed at determining molecular structure using methods such as small-angle X-ray and neutron scattering (SAXS and SANS). SAXS and... more
Understanding the structure-function relationship of biomolecules containing DNA has motivated experiments aimed at determining molecular structure using methods such as small-angle X-ray and neutron scattering (SAXS and SANS). SAXS and SANS are useful for determining macromolecular shape in solution, a process which benefits by using atomistic models that reproduce the scattering data. The variety of algorithms available for creating and modifying model DNA structures lack the ability to rapidly modify all-atom models to generate structure ensembles. This article describes a Monte Carlo algorithm for simulating DNA, not with the goal of predicting an equilibrium structure, but rather to generate an ensemble of plausible structures which can be filtered using experimental results to identify a sub-ensemble of conformations that reproduce the solution scattering of DNA macromolecules. The algorithm generates an ensemble of atomic structures through an iterative cycle in which B-DNA i...
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We describe a general method to use Monte Carlo simulation followed by torsion-angle molecular dynamics simulations to create ensembles of structures to model a wide variety of soft-matter biological systems. Our particular emphasis is... more
We describe a general method to use Monte Carlo simulation followed by torsion-angle molecular dynamics simulations to create ensembles of structures to model a wide variety of soft-matter biological systems. Our particular emphasis is focused on modeling low-resolution small-angle scattering and reflectivity structural data. We provide examples of this method applied to HIV-1 Gag protein and derived fragment proteins, TraI protein, linear B-DNA, a nucleosome core particle, and a glycosylated monoclonal antibody. This procedure will enable a large community of researchers to model low-resolution experimental data with greater accuracy by using robust physics based simulation and sampling methods which are a significant improvement over traditional methods used to interpret such data.
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ABSTRACT Compositions Containing Nucleases and Chelators to Enhance the Recovery of Cells During Cell Separating Procedures
Research Interests: Chemistry, Molecular Dynamics Simulation, Small angle X-ray and neutron scattering, Neutron Diffraction, Medicine, and 7 moreMolecular modeling, Circular Dichroism, X ray diffraction, THEORETICAL AND COMPUTATIONAL CHEMISTRY, Protein Conformation, Structure activity Relationship, and Monte Carlo Method
Small-angle neutron scattering was employed to study protein crowding under freezing conditions that mimic those used in pharmaceutical processing.
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Calculating the scattering intensity of an N-atom system is a numerically exhausting O(N 2) task. A simple approximation technique that scales linearly with the number of atoms is presented. Using an exact expression for the scattering... more
Calculating the scattering intensity of an N-atom system is a numerically exhausting O(N 2) task. A simple approximation technique that scales linearly with the number of atoms is presented. Using an exact expression for the scattering intensity I(q) at a given wavevector q, the rotationally averaged intensity I(q) is computed by evaluating I(q) in several scattering directions. The orientations of the q vectors are taken from a quasi-uniform spherical grid generated by the golden ratio. Using various biomolecules as examples, this technique is compared with an established multipole expansion method. For a given level of speed, the technique is more accurate than the multipole expansion for anisotropically shaped molecules, while comparable in accuracy for globular shapes. The processing time scales sub-linearly in N when the atoms are identical and lie on a lattice. The procedure is easily implemented and should accelerate the analysis of small-angle scattering data.
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Research Interests: Chemistry, Small angle X-ray and neutron scattering, Small Angle X Ray Scattering, Biophysical Chemistry, Medicine, and 11 moreBiological Sciences, Humans, Viscosity, Physical sciences, Monoclonal Antibodies, CHEMICAL SCIENCES, Electrolytes, X ray diffraction, Solutions, Salts, and Protein aggregates
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Passage of specific protein solutions through certain pumps, tubing, and/or filling nozzles can result in the production of unwanted subvisible protein particles (SVPs). In this work, surface-mediated SVP formation was investigated.... more
Passage of specific protein solutions through certain pumps, tubing, and/or filling nozzles can result in the production of unwanted subvisible protein particles (SVPs). In this work, surface-mediated SVP formation was investigated. Specifically, the effects of different solid interface materials, interfacial shear rates, and protein concentrations on SVP formation were measured for the National Institute of Standards and Technology monoclonal antibody (NISTmAb), a reference IgG1 monoclonal antibody (mAb). A stainless steel rotary piston pump was used to identify formulation and process parameters that affect aggregation, and a flow cell (alumina or stainless steel interface) was used to further investigate the effect of different interface materials and/or interfacial shear rates. SVP particles produced were monitored using flow microscopy or flow cytometry. Neutron reflectometry and a quartz crystal microbalance with dissipation monitoring were used to characterize adsorption and ...
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Protein-protein interactions in monoclonal antibody solutions are important for the stability of a therapeutic drug and directly influence viscosity in concentrated protein solutions. This study describes the use of small-angle scattering... more
Protein-protein interactions in monoclonal antibody solutions are important for the stability of a therapeutic drug and directly influence viscosity in concentrated protein solutions. This study describes the use of small-angle scattering to estimate protein-protein interactions at high concentrations of the IgG1 NISTmAb reference material and validate colloidal models for interacting molecules. In particular, we studied the colloidal stability of the NISTmAb at high protein concentrations and analyzed protein-protein interactions upon adding sodium chloride and its effect on viscosity. Isotropic colloidal models for interacting molecules were combined with an ensemble of atomistic structures from molecular simulation to account for the flexibility of the NISTmAb in solution. In histidine formulation buffer, net repulsive electrostatic interactions are important for the colloidal stability of the NISTmAb at high concentrations. Addition of sodium chloride increased the viscosity of ...
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Small-angle scattering is a powerful technique to study molecular conformation and interactions of proteins in solution and in amorphous solids. We have investigated the role of multiple protein configurations in the interaction... more
Small-angle scattering is a powerful technique to study molecular conformation and interactions of proteins in solution and in amorphous solids. We have investigated the role of multiple protein configurations in the interaction parameters derived from small-angle scattering for proteins in concentrated solutions. In order to account for the wide configurational space sampled by proteins, we generate ensembles of atomistic structures for lysozyme and monoclonal antibodies, representing globular and flexible proteins, respectively. While recent work has argued that a colloidal approach is inadequate to model proteins, because of the large configurational space that they sample in solution, we find a range of length scales where colloidal models can be used to describe solution scattering data while simultaneously accounting for structural flexibility. We provide insights to determine the length scales where isotropic colloidal models can be used, and find smoothly varying sets of int...