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SSRN 2024年

作者： Toopradab, Borwornlak Xie, Wanting Duan, Lian Hengphasatporn, Kowit Harada, Ryuhei Sinsulpsiri, Silpsiri Shigeta, Yasuteru Shi, Liyi Maitarad, Phornphimon Rungrotmongkol, Thanyada Program in Bioinformatics and Computational Biology Graduate School Chulalongkorn University Bangkok10330 Thailand Center of Excellence in Biocatalyst and Sustainable Biotechnology Department of Biochemistry Faculty of Science Chulalongkorn University Bangkok10330 Thailand Research Center of Nano Science and Technology Department of Chemistry College of Science Shanghai University Shanghai200444 China University of Tsukuba 1-1-1 Tennodai Ibaraki Tsukuba305-8577 Japan Graduate School of Pure and Applied Sciences University of Tsukuba 1-1-1 Tennodai Ibaraki305–8571 Japan Emerging Industries Institute Shanghai University Zhejiang Jiaxing314006 China

The global outbreak of the COVID-19 pandemic caused by the SARS-CoV-2 virus had led to profound respiratory health implications. This study focused on designing organoselenium-based inhibitors targeting the SARS-CoV-2 main protease (Mpro). The ligand-binding pathway sampling method based on parallel cascade selection molecular dynamics (LB-PaCS-MD) simulations was employed to elucidate plausible paths and conformations of ebselen, a synthetic organoselenium drug, within the Mpro catalytic site. Ebselen effectively engaged the active site, adopting proximity to H41 and interacting through the benzoisoselenazole ring in a π-π T-shaped arrangement, with an additional π-sulfur interaction with C145. In addition, the ligand-based drug design using the QSAR with GFA-MLR, RF, and ANN models were employed for biological activity prediction. The QSAR-ANN model showed robust statistical performance, with an R2training exceeding 0.98 and an RMSEtest of 0.21, indicating its suitability for predicting biological activities. Integration the ANN model with the LB-PaCS-MD insights enabled the rational design of novel compounds anchored in the ebselen core structure, identifying promising candidates with favorable predicted IC50 values. The designed compounds exhibited suitable drug-like characteristics and adopted an active conformation similar to ebselen, inhibiting Mpro function. These findings represent a synergistic approach merging ligand and structure-based drug design;with the potential to guide experimental synthesis and enzyme assay testing. © 2024, The Authors. All rights reserved.

关键词： Coronavirus

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Tessellated granular metamaterials with tunable elastic moduli

arXiv

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arXiv 2023年

作者： Pashine, Nidhi Wang, Dong Zhang, Jerry Patiballa, Sree Kalyan Witthaus, Sven Shattuck, Mark D. O’Hern, Corey S. Kramer-Bottiglio, Rebecca Department of Mechanical Engineering & Materials Science Yale University New HavenCT06520 United States Department of Physics Yale University New HavenCT06520 United States Department of Applied Physics Yale University New HavenCT06520 United States Graduate Program in Computational Biology & Bioinformatics Yale University New HavenCT06520 United States Benjamin Levich Institute Physics Department The City College of the City University of New York New YorkNY10031 United States

Most granular packings possess shear moduli (G) that increase with the applied external pressure, and bulk moduli (B) that increase or remain constant with pressure. This paper presents "tessellated" granular metamaterials for which both G and the ratio G/B decrease with increasing pressure. The granular metamaterials are made from flexible tessellations forming a ring of closed cells, each containing a small number of solid particles. For under-constrained tessellations, the dominant contributions to G and B are the particle-particle and particle-cell interactions. With specific particle configurations in the cells, we limit the number of possible particle rearrangements to achieve decreasing G as we increase the pressure difference between the inside and outside of the tessellation, leading to G/B 1 at large pressures. We further study tessellated granular metamaterials with cells containing a single particle and many particles to determine the variables that control the mechanical response of particle-filled tessellations as a function of pressure. © 2023, CC BY.

关键词： Metamaterials

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The impact of breast radiotherapy on the tumor genome and immune ecosystem

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Cell Reports 2025年第5期44卷 115703页

作者： Aislyn Schalck Tuan Tran Jianzhuo Li Emi Sei Shanshan Bai Min Hu Jerome Lin Scott J. Bright Samuel Reddick Fei Yang Harsh Batra Alejandro Contreras Maria Gabriela Raso Michael C. Stauder Karen E. Hoffman Jay P. Reddy Kevin T. Nead Benjamin D. Smith Gabriel O. Sawakuchi Wendy A. Woodward Stephanie S. Watowich Jennifer K. Litton Isabelle Bedrosian Elizabeth A. Mittendorf Huong Le-Petross Nicholas E. Navin Simona F. Shaitelman Department of Systems Biology University of Texas MD Anderson Cancer Center Houston TX 77030 USA Graduate School of Biological Sciences University of Texas Houston TX 770303 USA Department of Radiation Physics University of Texas MD Anderson Cancer Center Houston TX 77030 USA Department of Breast Radiation Oncology University of Texas MD Anderson Cancer Center Houston TX 77030 USA Vanderbilt University School of Medicine Nashville TN 37232 USA Department of Translational Molecular Pathology University of Texas MD Anderson Cancer Center Houston TX 77030 USA Janssen China Research & Development Johnson&Johnson Shanghai 201210 China Department of Anatomical Pathology University of Texas MD Anderson Cancer Center Houston TX 77030 USA Department of Epidemiology University of Texas MD Anderson Cancer Center Houston TX 77030 USA Department of Immunology University of Texas MD Anderson Cancer Center Houston TX 77030 USA Department of Breast Medical Oncology University of Texas MD Anderson Cancer Center Houston TX 77030 USA Department of Breast Surgical Oncology University of Texas MD Anderson Cancer Center Houston TX 77030 USA Division of Breast Surgery Department of Surgery Brigham and Women’s Hospital Boston MA 02115 USA Breast Oncology Program Dana-Farber Brigham Cancer Center Boston MA 02115 USA Harvard Medical School Boston MA 02115 USA Department of Breast Imaging University of Texas MD Anderson Cancer Center Houston TX 77030 USA Department of Bioinformatics and Computational Biology University of Texas MD Anderson Cancer Center Houston TX 77030 USA

Radiotherapy is a pillar of breast cancer treatment; however, it remains unclear how radiotherapy modulates the tumor microenvironment. We investigated this question in a cohort of 20 patients with estrogen-receptor positive (ER+) breast tumors who received neoadjuvant radiotherapy. Tumor biopsies were collected before and 7 days postradiation. Single-cell DNA sequencing (scDNA-seq) and scRNA-seq were conducted on 8 and 11 patients, respectively, at these two time points. The scRNA data showed increased infiltration of naive-like CD4 T cells and an early, activated CD8 T cell population following radiotherapy. Radiotherapy also eliminated existing cytotoxic T cells and resulted in myeloid cell increases. In tumor cells, the scDNA-seq data showed a high genomic selection of subclones in half of the patients with high ER expression, while the remaining number had low genomic selection and an interferon response. Collectively, these data provide insight into the impact of radiotherapy in ER+ breast cancer patients.

关键词： single cell genomics breast cancer radiation tumor microenvironment

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Hypostatic jammed packings of frictionless nonspherical particles

arXiv

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arXiv 2017年

作者： VanderWerf, Kyle Jin, Weiwei Shattuck, Mark D. O'Hern, Corey S. Department of Physics Yale University New HavenCT06520 United States Benjamin Levich Institute and Physics Department City College of New York New YorkNY10031 United States Department of Mechanics and Engineering Science Peking University Beijing100871 China Department of Mechanical Engineering & Materials Science Yale University New HavenCT06520 United States Department of Applied Physics Yale University New HavenCT06520 United States Graduate Program in Computational Biology and Bioinformatics Yale University New HavenCT06520 United States

We perform computational studies of static packings of a variety of nonspherical particles including circulo-lines, circulo-polygons, ellipses, asymmetric dimers, dumbbells, and others to determine which shapes form packings with fewer contacts than degrees of freedom (hypostatic packings) and which have equal numbers of contacts and degrees of freedom (isostatic packings), and to understand why hypostatic packings of nonspherical particles can be mechanically stable despite having fewer contacts than that predicted from naïve constraint counting. To generate highly accurate force- and torque-balanced packings of circulo-lines and -polygons, we developed an interparticle potential that gives continuous forces and torques as a function of the particle coordinates. We show that the packing fraction and coordination number at jamming onset obey a master-like form for all of the nonspherical particle packings we studied when plotted versus the particle asphericity A, which is proportional to the ratio of the squared perimeter to the area of the particle. Further, the eigenvalue spectra of the dynamical matrix for packings of different particle shapes collapse when plotted at the same A. For hypostatic packings of nonspherical particles, we verify that the number of "quartic" modes along which the potential energy increases as the fourth power of the perturbation amplitude matches the number of missing contacts relative to the isostatic value. We show that the fourth derivatives of the total potential energy in the directions of the quartic modes remain nonzero as the pressure of the packings is decreased to zero. In addition, we calculate the principal curvatures of the inequality constraints for each contact in circulo-line packings and identify specific types of contacts with inequality constraints that possess convex curvature. These contacts can constrain multiple degrees of freedom and allow hypostatic packings of nonspherical particles to be mechanically stable. C

关键词： Degrees of freedom (mechanics)

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Assessment of scoring functions for computational models of protein-protein interfaces

arXiv

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arXiv 2024年

作者： Sumner, Jacob Meng, Grace Brandt, Naomi Grigas, Alex T. Córdoba, Andrés Shattuck, Mark D. O’Hern, Corey S. Graduate Program in Computational Biology and Bioinformatics Yale University New HavenCT06520 United States Integrated Graduate Program in Physical and Engineering Biology Yale University New HavenCT06520 United States Department of Chemistry Yale University New HavenCT06520 United States Department of Physics Yale University New HavenCT06520 United States Department of Chemistry Duke University DurhamNC27708 United States Department of Physics Duke University DurhamNC27708 United States Benjamin Levich Institute Physics Department City College of New York New YorkNY10031 United States Department of Mechanical Engineering and Materials Science Yale University New HavenCT06520 United States Department of Applied Physics Yale University New HavenCT06520 United States

A goal of computational studies of protein-protein interfaces (PPIs) is to predict the binding site between two monomers that form a heterodimer. The simplest version of this problem is to rigidly re-dock the bound forms of the monomers, which involves generating computational models of the heterodimer and then scoring them to determine the most native-like models. Scoring functions have been assessed previously using rank- and classification-based metrics, however, these methods are sensitive to the number and quality of models in the scoring function training set. We assess the accuracy of seven PPI scoring functions by comparing their scores to a measure of structural similarity to the x-ray crystal structure (i.e. the DockQ score) for a non-redundant set of heterodimers from the Protein Data Bank. For each heterodimer, we generate re-docked models uniformly sampled over DockQ and calculate the Spearman correlation between the PPI scores and DockQ. For some targets, the scores and DockQ are highly correlated;however, for many targets, there are weak correlations. Several physical features can explain the difference between difficult- and easy-to-score targets. For example, strong correlations exist between the score and DockQ for targets with highly intertwined monomers and many interface contacts. We also develop a new score based on only three physical features that matches or exceeds the performance of current PPI scoring functions. These results emphasize that PPI prediction can be improved by focusing on correlations between the PPI score and DockQ and incorporating more discriminating physical features into PPI scoring functions. © 2024, CC BY.

关键词： Monomers

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Current md forcefields fail to capture key features of protein structure and fluctuations: a case study of cyclophilin a and t4 lysozyme

arXiv

引用

arXiv 2020年

作者： Mei, Zhe Grigas, Alex T. Treado, John D. Corres, Gabriel Melendez Vuorte, Maisa Sammalkorpi, Maria Regan, Lynne Levine, Zachary A. O’Hern, Corey S. Department of Chemistry Yale University New HavenCT06520 United States Integrated Graduate Program in Physical and Engineering Biology Yale University New HavenCT06520 United States Graduate Program in Computational Biology and Bioinformatics Yale University New HavenCT06520 United States Department of Mechanical Engineering and Materials Science Yale University New HavenCT06520 United States Department of Biology UPR Humacao Puerto RicoHumacao00792 Puerto Rico Department of Chemistry and Materials Science School of Chemical Engineering Aalto University Aalto Finland Department of Bioproducts and Biosystems School of Chemical Engineering Aalto University Aalto Finland Institute of Quantitative Biology Biochemistry and Biotechnology Center for Synthetic and Systems Biology School of Biological Sciences University of Edinburgh Edinburgh United Kingdom Department of Pathology Yale School of Medicine New HavenCT06520 United States Department of Molecular Biophysics and Biochemistry Yale University New HavenCT06520 United States Department of Physics Yale University New HavenCT06520 United States Department of Applied Physics Yale University New HavenCT06520 United States

Globular proteins undergo thermal fluctuations in solution, while maintaining an overall well-defined folded structure. In particular, studies have shown that the core structure of globular proteins differs in small, but significant ways when they are solved by x-ray crystallography versus solution-based NMR spectroscopy. Given these discrepancies, it is unclear whether molecular dynamics (MD) simulations can accurately recapitulate protein conformations. We therefore perform extensive MD simulations across multiple force fields and sampling techniques to investigate the degree to which computer simulations can capture the ensemble of conformations observed in experiments. By analyzing fluctuations in the atomic coordinates and core packing, we show that conformations sampled in MD simulations both move away from and sample a larger conformational space than the ensemble of structures observed in NMR experiments. However, we find that adding inter-residue distance restraints that match those obtained via Nuclear Overhauser Effect measurements enables the MD simulations to sample more NMR-like conformations, though significant differences between the core packing features in restrained MD and the NMR ensemble remain. Given that the protein structures obtained from the MD simulations possess smaller and less dense protein cores compared to those solved by NMR, we suggest that future improvements to MD forcefields should aim to increase the packing of hydrophobic residues in protein cores. © 2020, CC BY.

关键词： Molecular dynamics

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Contact network changes in ordered and disordered disk packings

arXiv

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arXiv 2020年

作者： Tuckman, Philip J. VanderWerf, Kyle Yuan, Ye Zhang, Shiyun Zhang, Jerry Shattuck, Mark D. O’Hern, Corey S. Department of Physics Yale University New HavenCT06520 United States Department of Mechanics and Engineering Science College of Engineering Peking University Beijing100871 China Department of Mechanical Engineering and Materials Science Yale University New HavenCT06520 United States Benjamin Levich Institute and Physics Department City College of New York New YorkNY10031 United States Department of Physics Yale University Department of Applied New HavenCT06520 United States Graduate Program in Computational Biology and Bioinformatics Yale University New HavenCT06520 United States

We investigate the mechanical response of packings of purely repulsive, frictionless disks to quasistatic deformations. The deformations include simple shear strain at constant packing fraction and at constant pressure, "polydispersity" strain (in which we change the particle size distribution) at constant packing fraction and at constant pressure, and isotropic compression. For each deformation, we show that there are two classes of changes in the interparticle contact networks: jump changes and point changes. Jump changes occur when a contact network becomes mechanically unstable, particles "rearrange", and the potential energy (when the strain is applied at constant packing fraction) or enthalpy (when the strain is applied at constant pressure) and all derivatives are discontinuous. During point changes, a single contact is either added to or removed from the contact network. For repulsive linear spring interactions, second- and higher-order derivatives of the potential energy/enthalpy are discontinuous at a point change, while for Hertzian interactions, third- and higher-order derivatives of the potential energy/enthalpy are discontinuous. We illustrate the importance of point changes by studying the transition from a hexagonal crystal to a disordered crystal induced by applying polydispersity strain. During this transition, the system only undergoes point changes, with no jump changes. We emphasize that one must understand point changes, as well as jump changes, to predict the mechanical properties of jammed packings. Copyright © 2020, The Authors. All rights reserved.

关键词： Potential energy

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Universal mechanical response of metallic glasses during strain-rate-dependent uniaxial compression

arXiv

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arXiv 2022年

作者： Jin, Weiwei Datye, Amit Schwarz, Udo D. Shattuck, Mark D. O'Hern, Corey S. Department of Mechanical Engineering and Materials Science Yale University New HavenCT06520 United States Department of Chemical and Environmental Engineering Yale University New HavenCT06520 United States Benjamin Levich Institute Physics Department The City College of New York New YorkNY10031 United States Department of Physics Yale University New HavenCT06520 United States Department of Applied Physics Yale University New HavenCT06520 United States Graduate Program in Computational Biology and Bioinformatics Yale University New HavenCT06520 United States

Experimental data on the compressive strength σmax versus strain rate Ε eng for metallic glasses undergoing uniaxial compression shows significantly different behavior for different alloys. For some metallic glasses, σmax decreases with increasing Ε eng, for others, σmax increases with increasing Ε eng, and for others σmax versus Ε eng is nonmonotonic. Using numerical simulations of metallic glasses undergoing uniaxial compression at nonzero strain rate and temperature, we show that they obey a universal relation for the compressive strength versus temperature, which determines their mechanical response. At low Ε eng, increasing strain rate leads to increases in temperature and decreases in σmax∗, whereas at high Ε eng, increasing strain rate leads to decreases in temperature and increases in σmax∗. This non-monotonic behavior of σmax∗ versus temperature causes the nonmonotonic behavior of σmax∗ versus Ε eng. Variations in the internal dissipation change the characteristic strain rate at which the nonmonotonic behavior occurs. These results are general for a wide range of metallic glasses with different atomic interactions, damping coefficients, and chemical compositions. © 2022, CC BY.

关键词： Strain rate

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Jammed packings of 3D superellipsoids with tunable packing fraction, contact number, and ordering

arXiv

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arXiv 2019年

作者： Yuan, Ye VanderWerf, Kyle Shattuck, Mark D. O’Hern, Corey S. Department of Mechanics and Engineering Science College of Engineering Peking University Beijing100871 China Department of Mechanical Engineering and Materials Science Yale University New HavenCT06520 United States Department of Physics Yale University New HavenCT06520 United States Benjamin Levich Institute and Physics Department City College of New York New YorkNY10031 United States Department of Applied Physics Yale University New HavenCT06520 United States Graduate Program in Computational Biology and Bioinformatics Yale University New HavenCT06520 United States

We carry out numerical studies of static packings of frictionless superellipsoidal particles in three spatial dimensions. We consider more than 200 different particle shapes by varying the three shape parameters that define superellipsoids. We characterize the structural and mechanical properties of both disordered and ordered packings using two packing-generation protocols. We perform athermal quasi-static compression simulations starting from either random, dilute configurations (Protocol 1) or thermalized, dense configurations (protocol 2), which allows us to tune the orientational order of the packings. In general, we find that the contact numbers at jamming onset for superellipsoid packings are hypostatic, with zJ f and df = 5 or 6 depending on whether the particles are axi-symmetric or not. Over the full range of orientational order, we find that the number of quartic modes of the dynamical matrix for the packings always matches the number of missing contacts relative to the isostatic value. This result suggests that there are no mechanically redundant contacts for ordered, yet hypostatic packings of superellipsoidal particles. Additionally, we find that the packing fraction at jamming onset for diordered packings of superellipsoidal particles can be collapsed using two particle shape parameters, e.g. the asphericity A and reduced aspect ratio β of the particles. Copyright © 2019, The Authors. All rights reserved.

关键词： Jamming

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Local and global measures of the shear moduli of jammed disk packings

arXiv

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arXiv 2023年

作者： Zhang, Shiyun Jin, Weiwei Wang, Dong Xu, Ding Zhang, Jerry Shattuck, Mark D. O’Hern, Corey S. Department of Physics University of Science and Technology of China Anhui Hefei230026 China Department of Mechanical Engineering and Materials Science Yale University New HavenCT06520 United States Benjamin Levich Institute and Physics Department The City College of New York New YorkNY10031 United States Department of Physics Yale University New HavenCT06520 United States Department of Applied Physics Yale University New HavenCT06520 United States Graduate Program in Computational Biology and Bioinformatics Yale University New HavenCT06520 United States

Strain-controlled isotropic compression gives rise to jammed packings of repulsive, frictionless disks with either positive or negative global shear moduli. We carry out computational studies to understand the contributions of the negative shear moduli to the mechanical response of jammed disk packings. We first decompose the ensemble-averaged, global shear modulus as hGi = (1 − F−)hG+i + F−hG−i, where F− is the fraction of jammed packings with negative shear moduli and hG+i and hG−i are the average values from packings with positive and negative moduli, respectively. We show that hG+i and h|G−|i obey different power-law scaling relations above and below pN2 ∼ 1. For pN2 > 1, both hG+iN and h|G−|iN ∼ (pN2)β, where β ∼ 0.5 for repulsive linear spring interactions. Despite this, hGiN ∼ (pN2)β0 with β0 & 0.5 due to the contributions from packings with negative shear moduli. We show further that the probability distribution of global shear moduli P(G) collapses at fixed pN2 and different values of p and N. We calculate analytically that P(G) is a Gamma distribution in the pN2 1 limit. As pN2 increases, the skewness of P(G) decreases and P(G) becomes a skew-normal distribution with negative skewness in the pN2 1 limit. We also partition jammed disk packings into subsystems using Delanunay triangulation of the disk centers to calculate local shear moduli. We show that the local shear moduli defined from groups of adjacent triangles can be negative even when G > 0. The spatial correlation function of local shear moduli C(~r) displays weak correlations for pn2sub −2, where nsub is the number of particles within each subsystem. However, C(~r) begins to develop long-ranged spatial correlations with four-fold angular symmetry for pn2sub & 10−2 © 2023, CC BY-NC-ND.

关键词： Elastic moduli

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