A new equation of state for homo-polymers in dissipative particle dynamics.

A chain-revised Groot-Warren equation of state (crGW-EOS) was developed and tested to describe systems of homo-oligomeric chains in the framework of dissipative particle dynamics (DPD). First, thermodynamic perturbation theory is applied to introduce correction terms that account for the reduction in pressure with an increasing number of bonds at constant bead number density. Then, this EOS is modified by introducing a set of switching functions that yields an accurate second virial coefficient in the low-density limit. The crGW-EOS offers several improvements over the revised Groot-Warren equation of state and Groot-Warren equation of state for chain molecules. We tested the crGW-EOS by using it to predict the pressure of oligomeric systems and the B2 virial coefficient of chain DPD particles for a range of bond lengths. Additionally, a method is developed for determining the strength of cross-interaction parameters between chains of different compositions and sizes and for thermal and athermal mixtures. We explored how different levels of coarse-graining affect the upper-critical solution temperature.

Probing Additive Loading in the Lamellar Phase of a Nonionic Surfactant: Gibbs Ensemble Monte Carlo Simulations Using the SDK Force Field.

Understanding solute uptake into soft microstructured materials, such as bilayers and worm-like and spherical micelles, is of interest in the pharmaceutical, agricultural, and personal care industries. To obtain molecular-level insight on the effects of solutes loading into a lamellar phase, we utilize the Shinoda-Devane-Klein (SDK) coarse-grained force field in conjunction with configurational-bias Monte Carlo simulations in the osmotic Gibbs ensemble. The lamellar phase is comprised of a bilayer formed by triethylene glycol mono- n-decyl ether (C10E3) surfactants surrounded by water with a 50:50 surfactant/water weight ratio. We study both the unary adsorption isotherm and the effects on bilayer structure and stability caused by n-nonane, 1-hexanol, and ethyl butyrate at several different reduced reservoir pressures. The nonpolar n-nonane molecules load near the center of the bilayer. In contrast, the polar 1-hexanol and ethyl butyrate molecules both load with their polar bead close to the surfactant head groups. Near the center of the bilayer, none of the solute molecules exhibits a significant orientational preference. Solute molecules adsorbed near the polar groups of the surfactant chains show a preference for orientations perpendicular to the interface, and this alignment with the long axis of the surfactant molecules is most pronounced for 1-hexanol. Loading of n-nonane leads to an increase of the bilayer thickness, but does not affect the surface area per surfactant. Loading of polar additives leads to both lateral and transverse swelling. The reduced Henry's law constants of adsorption (expressed as a molar ratio of additive to surfactant per reduced pressure) are 0.23, 1.4, and 14 for n-nonane, 1-hexanol, and ethyl butyrate, respectively, and it appears that the SDK force field significantly overestimates the ethyl butyrate-surfactant interactions.

Effect of 10.5 M Aqueous Urea on Helicobacter pylori Urease: A Molecular Dynamics Study.

The effects of a 10.5 M solution of aqueous urea on Helicobacter pylori urease were investigated over the course of a 500 ns molecular dynamics (MD) simulation. The enzyme was solvated by 25321 water molecules, and additionally, 4788 urea molecules were added to the solution. Although concentrated urea solutions are known laboratory denaturants, the protein secondary structure is retained throughout the simulation largely because of the short simulation time (urea denaturation occurs on the millisecond time scale). The relatively constant solvent accessible surface area over the last 400 ns of the simulation further confirms the overall lack of denaturation. The wide-open flap state observed previously in Klebsiella areogenes urease [Roberts, B. P., et al. (2012) J. Am. Chem. Soc. 134, 9934] and H. pylori [Minkara, M. S., et al. (2014) J. Chem. Theory Comput. 10, 1852-1862] was also identified in this aqueous urea simulation. Over the course of the trajectory, we were able to observe urea molecules entering the active site in proportions related to the extent of opening of the active site-covering flap. Furthermore, urea molecules were observed to approach the pentacoordinate Ni(2+) ion in position to bind in a manner consistent with the proposed initial coordination step of the hydrolysis mechanism. We also observed a specific and unique pattern in the regions of the protein with a high root-mean-square fluctuation (rmsf). The high-rmsf regions in the ß-chain form a horseshoelike arrangement surrounding the active site-covering flap on the surface of the protein. We hypothesize that the function of these regions is to both attract and shuttle urea toward the loop of the active site-covering flap before entry into the cavity. Indeed, urea is observed to interact with these regions for extended periods of simulation time before active site ingress.

Reduction of urease activity by interaction with the flap covering the active site.

With the increasing appreciation for the human microbiome coupled with the global rise of antibiotic resistant organisms, it is imperative that new methods be developed to specifically target pathogens. To that end, a novel computational approach was devised to identify compounds that reduce the activity of urease, a medically important enzyme of Helicobacter pylori, Proteus mirabilis, and many other microorganisms. Urease contains a flexible loop that covers its active site; Glide was used to identify small molecules predicted to lock this loop in an open conformation. These compounds were screened against the model urease from Klebsiella aerogenes, and the natural products epigallocatechin and quercetin were shown to inhibit at low and high micromolar concentrations, respectively. These molecules exhibit a strong time-dependent inactivation of urease that was not due to their oxygen sensitivity. Rather, these compounds appear to inactivate urease by reacting with a specific Cys residue located on the flexible loop. Substitution of this cysteine by alanine in the C319A variant increased the urease resistance to both epigallocatechin and quercetin, as predicted by the computational studies. Protein dynamics are integral to the function of many enzymes; thus, identification of compounds that lock an enzyme into a single conformation presents a useful approach to define potential inhibitors.

Implementation of Protocols To Enable Doctoral Training in Physical and Computational Chemistry of a Blind Graduate Student.

There exists a sparse representation of blind and low-vision students in science, technology, engineering and mathematics (STEM) fields. This is due in part to these individuals being discouraged from pursuing STEM degrees as well as a lack of appropriate adaptive resources in upper level STEM courses and research. Mona Minkara is a rising fifth year graduate student in computational chemistry at the University of Florida. She is also blind. This account presents efforts conducted by an expansive team of university and student personnel in conjunction with Mona to adapt different portions of the graduate student curriculum to meet Mona's needs. The most important consideration is prior preparation of materials to assist with coursework and cumulative exams. Herein we present an account of the first four years of Mona's graduate experience hoping this will assist in the development of protocols for future blind and low-vision graduate students in computational chemistry.

Universal pictures: A lithophane codex helps teenagers with blindness visualize nanoscopic systems.

People with blindness have limited access to the high-resolution graphical data and imagery of science. Here, a lithophane codex is reported. Its pages display tactile and optical readouts for universal visualization of data by persons with or without eyesight. Prototype codices illustrated microscopy of butterfly chitin-from N-acetylglucosamine monomer to fibril, scale, and whole insect-and were given to high schoolers from the Texas School for the Blind and Visually Impaired. Lithophane graphics of Fischer-Spier esterification reactions and electron micrographs of biological cells were also 3D-printed, along with x-ray structures of proteins (as millimeter-scale 3D models). Students with blindness could visualize (describe, recall, distinguish) these systems-for the first time-at the same resolution as sighted peers (average accuracy = 88%). Tactile visualization occurred alongside laboratory training, synthesis, and mentoring by chemists with blindness, resulting in increased student interest and sense of belonging in science.

Corrigendum to "Elucidating the enhanced binding affinity of a double mutant SP-D with trimannose on the influenza A virus using molecular dynamics" [Comput. Struct. Biotechnol. J. 20 (2022) 4984-5000].

[This corrects the article DOI: 10.1016/j.csbj.2022.08.045.].

Multiple drugs and multiple targets: an analysis of the electrostatic determinants of binding between non-nucleoside HIV-1 reverse transcriptase inhibitors and variants of HIV-1 RT.

We present a systematic, computational analysis of the electrostatic component of binding of three HIV-1 RT inhibitors-nevirapine (NVP), efavirenz (EFV), and the recently approved rilpivirine (RPV)-to wild-type (WT) and mutant variants of RT. Electrostatic charge optimization was applied to determine how suited each molecule's charge distribution is for binding WT and individual mutants of HIV-1 RT. Although the charge distributions of NVP and EFV are rather far from being optimal for tight binding, RPVs charge distribution is close to the theoretical, optimal charge distribution for binding WT HIV-1 RT, although slight changes in charge can dramatically impact binding energetics. Moreover, toward the L100I/K103N double mutant, RPVs charge distribution is quite far from optimal. We also determine the contributions of chemical moieties on each molecule toward the electrostatic component of binding and show that different regions of a drug molecule may be used for recognition by different RT variants. The electrostatic contributions of certain RT residues toward drug binding are also computed to highlight critical residues for each interaction. Finally, the charge distribution of RPV is optimized to promiscuously bind to three RT variants rather than to each one in turn, with the resulting charge distribution being a compromise between the optimal charge distributions to each individual variant. Taken together, this work demonstrates that even in a binding site considered quite hydrophobic, electrostatics play a subtle yet varying role that must be considered in designing next-generation molecules that recognize rapidly mutating targets.

Elucidating the enhanced binding affinity of a double mutant SP-D with trimannose on the influenza A virus using molecular dynamics.

Surfactant protein D (SP-D) is an essential component of the human pulmonary surfactant system, which is crucial in the innate immune response against glycan-containing pathogens, including Influenza A viruses (IAV) and SARS-CoV-2. Previous studies have shown that wild-type (WT) SP-D can bind IAV but exhibits poor antiviral activities. However, a double mutant (DM) SP-D consisting of two point mutations (Asp325Ala and Arg343Val) inhibits IAV more potently. Presently, the structural mechanisms behind the point mutations' effects on SP-D's binding affinity with viral surface glycans are not fully understood. Here we use microsecond-scale, full-atomistic molecular dynamics (MD) simulations to understand the molecular mechanism of mutation-induced SP-D's higher antiviral activity. We find that the Asp325Ala mutation promotes a trimannose conformational change to a more stable state. Arg343Val increases the binding with trimannose by increasing the hydrogen bonding interaction with Glu333. Free energy perturbation (FEP) binding free energy calculations indicate that the Arg343Val mutation contributes more to the increase of SP-D's binding affinity with trimannose than Asp325Ala. This study provides a molecular-level exploration of how the two mutations increase SP-D binding affinity with trimannose, which is vital for further developing preventative strategies for related diseases.

Nonane and Hexanol Adsorption in the Lamellar Phase of a Nonionic Surfactant: Molecular Simulations and Comparison to Ideal Adsorbed Solution Theory.

Adsorption of n-nonane/1-hexanol (C9/C6OH) mixtures into the lamellar phase formed by a 50/50 w/w triethylene glycol mono-n-decyl ether (C10E3)/water system was studied using configurational-bias Monte Carlo simulations in the osmotic Gibbs ensemble. The interactions were described by the Shinoda-Devane-Klein coarse-grained force field. Prior simulations probing single-component adsorption indicated that C9 molecules preferentially load near the center of the bilayer, increasing the bilayer thickness, whereas C6OH molecules are more likely to be found near the interface of the polar and nonpolar moieties, swelling the bilayer in the lateral dimension. Here, we extend this work to binary C9/C6OH adsorption to probe whether the difference in the spatial preferences may lead to a synergistic effect and enhanced loadings for the mixture. Comparing loading trends and the thermodynamics of binary adsorption to unary adsorption reveals that C9-C9 interactions lead to the largest enhancement, whereas C9-C6OH and C6OH-C6OH interactions are less favorable for this bilayer system. Ideal adsorbed solution theory yields satisfactory predictions of the binary loading.

Data for all: Tactile graphics that light up with picture-perfect resolution.

People who are blind do not have access to graphical data and imagery produced by science. This exclusion complicates learning and data sharing between sighted and blind persons. Because blind people use tactile senses to visualize data (and sighted people use eyesight), a single data format that can be easily visualized by both is needed. Here, we report that graphical data can be three-dimensionally printed into tactile graphics that glow with video-like resolution via the lithophane effect. Lithophane forms of gel electropherograms, micrographs, electronic and mass spectra, and textbook illustrations could be interpreted by touch or eyesight at ≥79% accuracy (n = 360). The lithophane data format enables universal visualization of data by people regardless of their level of eyesight.

The Influence of a Blind Professor in a Bioengineering Course.

Although there is increasing literature on blind and visually impaired students in science, technology, engineering, and mathematics (STEM), there is a prevalent gap in the literature regarding STEM educators who are blind or visually impaired. This account aims to partially fill this gap by presenting the methodology and implementation of teaching by Dr. Mona Minkara, a blind bioengineering professor, as well as the tangible outcomes of this approach. We discuss the efforts taken by Dr. Minkara and a team of access assistants to develop accessible methods for teaching a largely visual course, including the use of assistive technologies, such as alternative text, braille, and text-to-speech software. Outside perspectives from teaching assistants, access assistants, and students are also discussed. Student feedback was collected in an end-of-term survey and analyzed to obtain quantitative and qualitative data. Evidenced by student feedback on their experience, we demonstrate that Dr. Minkara's visual impairment altered student perceptions about blindness in education and led to a more interactive and engaging learning environment for her students. This evidence also shows that students were overwhelmingly in support of more blind educators in STEM. We present this account and share our developing toolbox to demonstrate that a career in higher education can (and should) be accessible if given the right modifications. Efforts aimed at broadening the participation of blind and visually impaired individuals in STEM education can continue to alter student perceptions and lead to enhanced learning environments, as well as encourage instructors to increase the accessibility of their own teaching. Supplementary Information: The online version contains supplementary material available at 10.1007/s43683-021-00052-1.

Molecular Dynamics Study of Helicobacter pylori Urease.

Helicobacter pylori have been implicated in an array of gastrointestinal disorders including, but not limited to, gastric and duodenal ulcers and adenocarcinoma. This bacterium utilizes an enzyme, urease, to produce copious amounts of ammonia through urea hydrolysis in order to survive the harsh acidic conditions of the stomach. Molecular dynamics (MD) studies on the H. pylori urease enzyme have been employed in order to study structural features of this enzyme that may shed light on the hydrolysis mechanism. A total of 400 ns of MD simulation time were collected and analyzed in this study. A wide-open flap state previously observed in MD simulations on Klebsiella aerogenes [Roberts et al. J. Am. Chem. Soc.2012, 134, 9934] urease has been identified in the H. pylori enzyme that has yet to be experimentally observed. Critical distances between residues on the flap, contact points in the closed state, and the separation between the active site Ni2+ ions and the critical histidine α322 residue were used to characterize flap motion. An additional flap in the active site was elaborated upon that we postulate may serve as an exit conduit for hydrolysis products. Finally we discuss the internal hollow cavity and present analysis of the distribution of sodium ions over the course of the simulation.

Analysis of fast boundary-integral approximations for modeling electrostatic contributions of molecular binding.

We analyze and suggest improvements to a recently developed approximate continuum-electrostatic model for proteins. The model, called BIBEE/I (boundary-integral based electrostatics estimation with interpolation), was able to estimate electrostatic solvation free energies to within a mean unsigned error of 4% on a test set of more than 600 proteins-a significant improvement over previous BIBEE models. In this work, we tested the BIBEE/I model for its capability to predict residue-by-residue interactions in protein-protein binding, using the widely studied model system of trypsin and bovine pancreatic trypsin inhibitor (BPTI). Finding that the BIBEE/I model performs surprisingly less well in this task than simpler BIBEE models, we seek to explain this behavior in terms of the models' differing spectral approximations of the exact boundary-integral operator. Calculations of analytically solvable systems (spheres and tri-axial ellipsoids) suggest two possibilities for improvement. The first is a modified BIBEE/I approach that captures the asymptotic eigenvalue limit correctly, and the second involves the dipole and quadrupole modes for ellipsoidal approximations of protein geometries. Our analysis suggests that fast, rigorous approximate models derived from reduced-basis approximation of boundary-integral equations might reach unprecedented accuracy, if the dipole and quadrupole modes can be captured quickly for general shapes.