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

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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

Identifying topologically associating domains using differential kernels

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arXiv 2023年

作者： Maisuradze, Luka King, Megan C. Surovtsev, Ivan V. Mochrie, Simon G.J. Shattuck, Mark D. O’Hern, Corey S. Department of Molecular Biophysics and Biochemistry Yale University New HavenCT United States Department of Cell Biology Yale School of Medicine New HavenCT United States Department of Physics Yale University New HavenCT United States Benjamin Levich Institute Physics Department The City College of New York New YorkNY United States Department of Mechanical Engineering and Materials Science Yale University New HavenCT United States Graduate Program in Computational Biology and Bioinformatics Yale University New HavenCT United States

Chromatin is a polymer complex of DNA and proteins that regulates gene expression. The three-dimensional (3D) structure and organization of chromatin controls DNA transcription and replication. High-throughput chromatin conformation capture techniques generate Hi-C maps that can provide insight into the 3D structure of chromatin. Hi-C maps can be represented as a symmetric matrix Aij, where each element represents the average contact probability or number of contacts between chromatin loci i and j. Previous studies have detected topologically associating domains (TADs), or self-interacting regions in Aij within which the contact probability is greater than that outside the region. Many algorithms have been developed to identify TADs within Hi-C maps. However, most TAD identification algorithms are unable to identify nested or overlapping TADs and for a given Hi-C map there is significant variation in the location and number of TADs identified by different methods. We develop a novel method to identify TADs, KerTAD, using a kernel-based technique from computer vision and image processing that is able to accurately identify nested and overlapping TADs. We benchmark this method against state-of-the-art TAD identification methods on both synthetic and experimental data sets. We find that the new method consistently has higher true positive rates (TPR) and lower false discovery rates (FDR) than all tested methods for both synthetic and manually annotated experimental Hi-C maps. The TPR for KerTAD is also largely insensitive to increasing noise and sparsity, in contrast to the other methods. We also find that KerTAD is consistent in the number and size of TADs identified across replicate experimental Hi-C maps for several organisms. Thus, KerTAD will improve automated TAD identification and enable researchers to better correlate changes in TADs to biological phenomena, such as enhancer-promoter interactions and disease states. © 2023, CC BY.

关键词： Topology

Iterative quantum optimization of spin glass problems with rapidly oscillating transverse fields

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arXiv 2024年

作者： Barton, Brandon Sagal, Jacob Feeney, Sean Grattan, George Patnaik, Pratik Oganesyan, Vadim Carr, Lincoln D. Kapit, Eliot Quantum Engineering Program Colorado School of Mines 1523 Illinois St GoldenCO80401 United States Department of Applied Mathematics and Statistics Colorado School of Mines 1500 Illinois St GoldenCO80401 United States Center for Computational Quantum Physics Flatiron Institute 162 5th Avenue New YorkNY10010 United States Department of Physics Colorado School of Mines 1523 Illinois St GoldenCO80401 United States Department of Computer Science Colorado School of Mines 1500 Illinois St GoldenCO80401 United States Department of Physics and Astronomy College of Staten Island City University of New York Staten IslandNY10314 United States Physics program and Initiative for the Theoretical Sciences The Graduate Center City University of New York New YorkNY10016 United States

In this work, we introduce a new iterative quantum algorithm, called Iterative Symphonic Tunneling for Satisfiability problems (IST-SAT), which solves quantum spin glass optimization problems using high-frequency oscillating transverse fields. IST-SAT operates as a sequence of iterations, in which bitstrings returned from one iteration are used to set spin-dependent phases in oscillating transverse fields in the next iteration. Over several iterations, the novel mechanism of the algorithm steers the system toward the problem ground state. We benchmark IST-SAT on sets of hard MAX-3-XORSAT problem instances with exact state vector simulation, and report polynomial speedups over trotterized adiabatic quantum computation (TAQC) and the best known semi-greedy classical algorithm. When IST-SAT is seeded with a sufficiently good initial approximation, the algorithm converges to exact solution(s) in a polynomial number of iterations. Our numerical results identify a critial Hamming radius(CHR), or quality of initial approximation, where the time-to-solution crosses from exponential to polynomial scaling in problem size. By combining IST-SAT with future classical or quantum approximation algorithms, larger gains may be achieved. The mechanism we present in this work thus presents a new path toward achieving quantum advantage in optimization. © 2024, CC BY.

关键词： Combinatorial optimization

In silico identification of a novel Cdc2-like kinase 2 (CLK2) inhibitor in triple negative breast cancer

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Protein science 2024年第6期33卷 e5004-e5004页

作者： Huang, Cheng-Chiao Hsu, Chia-Ming Chao, Min-Wu Hsu, Kai-Cheng Lin, Tony Eight Yen, Shih-Chung Tu, Huang-Ju Pan, Shiow-Lin Ph.D. Program for Cancer Molecular Biology and Drug Discovery College of Medical Science and Technology Taipei Medical University and Academia Sinica Taipei Taiwan Division of General Surgery Department of Surgery Taipei Medical University Hospital Taipei Taiwan Graduate Institute of Cancer Biology and Drug Discovery College of Medical Science and Technology Taipei Medical University Taipei Taiwan School of Medicine College of Medicine National Sun Yat-sen University Kaohsiung Taiwan Institute of Biopharmaceutical Sciences College of Medicine National Sun Yat-sen University Kaohsiung Taiwan The Doctoral Program of Clinical and Experimental Medicine College of Medicine National Sun Yat-sen University Kaohsiung Taiwan Ph.D. Program in Drug Discovery and Development Industry College of Pharmacy Taipei Medical University Taipei Taiwan TMU Research Center of Cancer Translational Medicine Taipei Medical University Taipei Taiwan TMU Research Center of Drug Discovery Taipei Medical University Taipei Taiwan Warshel Institute for Computational Biology The Chinese University of Hong Kong (Shenzhen) Guangdong Shenzhen China

Dysregulation of RNA splicing processes is intricately linked to tumorigenesis in various cancers, especially breast cancer. Cdc2-like kinase 2 (CLK2), an oncogenic RNA-splicing kinase pivotal in breast cancer, plays a significant role, particularly in the context of triple-negative breast cancer (TNBC), a subtype marked by substantial medical challenges due to its low survival rates. In this study, we employed a structure-based virtual screening (SBVS) method to identify potential CLK2 inhibitors with novel chemical structures for treating TNBC. Compound 670551 emerged as a novel CLK2 inhibitor with a 50% inhibitory concentration (IC₅₀) value of 619.7 nM. Importantly, Compound 670551 exhibited high selectivity for CLK2 over other protein kinases. Functionally, this compound significantly reduced the survival and proliferation of TNBC cells. Results from a cell-based assay demonstrated that this inhibitor led to a decrease in RNA splicing proteins, such as SRSF4 and SRSF6, resulting in cell apoptosis. In summary, we identified a novel CLK2 inhibitor as a promising potential treatment for TNBC therapy. © 2024 The Authors. Protein science published by Wiley Periodicals LLC on behalf of The Protein Society.

关键词： CLK2 drug discovery kinase inhibitor structure-based virtual screening triple-negative breast cancer

Mass Transport in a Highly Immiscible Alloy on Extended Shear Deformation

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SSRN

SSRN 2022年

作者： Song, Miao Liu, Jia Ma, Xiaolong Pang, Qin Olszta, Matthew J. Silverstein, Joshua Pallaka, Madhusudhan R. Sushko, Peter V. Mathaudhu, Suveen N. Powell, Cynthia Devaraj, Arun Gwalani, Bharat Physical and Computational Sciences Directorate Pacific Northwest National Laboratory 902 Battelle Boulevard RichlandWA99354 United States Energy and Environmental Directorate Pacific Northwest National Laboratory 902 Battelle Boulevard RichlandWA99354 United States Material Science and Engineering Program University of California Riverside RiversideCA92521 United States Colorado School of Mines 1500 Illinois St. GoldenCO8040 United States

Forced mixing to a single-phase or supersaturated solid solution (SSS) and its prerequisite microstructure evolution in immiscible systems has been a focus of research for fundamental science and practical applications. Controlling the formation of SSS by shear deformation could enable a material design beyond conventional equilibrium microstructure in immiscible systems. Here, a highly immiscible Cu-50 at. % Cr binary alloy (mixing enthalpy of ~ 20 kJ·mol-1) was employed to investigate the microstructure evolution and localized tendencies of SSS during severe shear deformation. Our results demonstrate the dislocation mediated microstructural refinement process in each phase of the binary alloy and the mechanisms associated with localized solute supersaturation as a function of shear strain. Pronounced grain refinement in the softer Cu phase occurs owing to the strain localization driving the preferential dynamic recrystallization. The grain refinement of the Cr phase, however, is enabled by the progressive evolution of grain lamination, splitting, and fragmentation as a function of shear strain. The solute supersaturation is found to be strongly dependent on the local environments that affect the dislocation activity, including the level of microstructure refinement, the interfacial orientation relationship, the mechanical incompatibility, and the localized preferential phase oxidation. Ab initio simulations confirm that it is more favorable to oxidize Cr than Cu at incoherent Cu/Cr interfaces, limiting the mass transport on an incoherent boundary. Our results unveil the mechanism underpinning the non-equilibrium mass transport in immiscible systems upon severe deformation that can be applied to produce immiscible alloys with superior mechanical properties. © 2022, The Authors. All rights reserved.

关键词： Tribology

Beyond trees: classification with sparse pairwise dependencies

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The Journal of Machine Learning Research

The Journal of Machine Learning Research 2020年第1期21卷 7728-7760页

作者： Yaniv Tenzer Amit Moscovich Mary Frances Dorn Boaz Nadler Clifford Spiegelman Department of Computer Science and Applied Mathematics Weizmann Institute of Science Rehovot Israel Program in Applied and Computational Mathematics Princeton University Princeton NJ Los Alamos National Laboratory Los Alamos NM Department of Statistics Texas A&M University College Station TX

Several classification methods assume that the underlying distributions follow tree-structured graphical models. Indeed, trees capture statistical dependencies between pairs of variables, which may be crucial to attaining low classification errors. In this setting, the optimal classifier is linear in the log-transformed univariate and bivariate densities that correspond to the tree edges. In practice, observed data may not be well approximated by trees. Yet, motivated by the importance of pairwise dependencies for accurate classification, here we propose to approximate the optimal decision boundary by a sparse linear combination of the univariate and bivariate log-transformed densities. Our proposed approach is semi-parametric in nature: we non-parametrically estimate the univariate and bivariate densities, remove pairs of variables that are nearly independent using the Hilbert-Schmidt independence criterion, and finally construct a linear SVM using the retained log-transformed densities. We demonstrate on synthetic and real data sets, that our classifier, named SLB (sparse log-bivariate density), is competitive with other popular classification methods.

关键词： binary classification graphical model Bayesian network sparsity semi-parametric

Modeling phonon-mediated quasiparticle poisoning in superconducting qubit arrays

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arXiv 2024年

作者： Yelton, Eric Larson, Clayton P. Iaia, Vito Dodge, Kenneth La Magna, Guglielmo Baity, Paul G. Pechenezhskiy, Ivan V. McDermott, Robert Kurinsky, Noah A. Catelani, Gianluigi Plourde, Britton L.T. Department of Physics Syracuse University SyracuseNY13244-1130 United States Intelligence Community Postdoctoral Research Fellowship Program Department of Physics Syracuse University SyracuseNY13244-1130 United States Forschungszentrum Jülich Jülich52425 Germany Quantum Research Center Technology Innovation Institute Abu Dhabi9639 United Arab Emirates Computational Science Initiative Brookhaven National Laboratory UptonNY11973 United States Department of Physics University of Wisconsin-Madison MadisonWI53706 United States Kavli Institute for Particle Astrophysics and Cosmology SLAC National Accelerator Laboratory Menlo ParkCA94025 United States

Correlated errors caused by ionizing radiation impacting superconducting qubit chips are problematic for quantum error correction. Such impacts generate quasiparticle (QP) excitations in the qubit electrodes, which temporarily reduce qubit coherence significantly. The many energetic phonons produced by a particle impact travel efficiently throughout the device substrate and generate quasiparticles with high probability, thus causing errors on a large fraction of the qubits in an array simultaneously. We describe a comprehensive strategy for the numerical simulation of the phonon and quasiparticle dynamics in the aftermath of an impact. We compare the simulations with experimental measurements of phonon-mediated QP poisoning and demonstrate that our modeling captures the spatial and temporal footprint of the QP poisoning for various configurations of phonon downconversion structures. We thus present a path forward for the operation of superconducting quantum processors in the presence of ionizing radiation. Copyright © 2024, The Authors. All rights reserved.

关键词： Qubits

Rabi antenna using microstrip add-drop multiplexer for electron warp speed investigation

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Chinese Optics Letters 2022年第7期20卷 80-87页

作者： Somchat Sonasang Prakasit Prabpal Piya Sirikan Pratimakorn Hakaew Nhat Truong Pham Preecha Yupapin Kanad Ray Sarawoot Boonkirdram Department of Electronic Technology Faculty of Industrial TechnologyNakhon Phanom UniversityNakhon Phanom 48000Thailand Department of Electrical Technology School of Industrial TechnologySakonnakhon Technical CollegeInstitute of Vocational Education Northeastern Region 2Sakonnakhorn 47000Thailand Division of Computational Mechatronics Institute for Computational ScienceTon Duc Thang UniversityHo Chi Minh City 72915Vietnam Faculty of Electrical and Electronics Engineering Ton Duc Thang UniversityHo Chi Minh City 72915Vietnam Amity School of Applied Sciences Amity University RajasthanJaipurIndia Faubert Lab Universitéde MontréalH3T 1P1 MontréalCanada Facultad de CienciasFisico-Matematicas Benemérita Universidad Autónoma de PueblaAv.San Claudio y Av.18 surCol.San Manuel Ciudad UniversitariaPuebla Pue 72570Mexico Program of Electrical and Electronics Faculty of Industrial TechnologySakon Nakhon Rajabhat UniversitySakon Nakhon 47000Thailand

This work presents experimental results of Rabi antenna characteristics using the coupled line microstrip *** was constructed by a modified coupled line microstrip four-port network,which is known as an add-drop *** driven AC input enters the device via an input port using the suitable frequency and coupled line microstrip ring *** multilevel system is generated by a wave-particle aspect before the two-level system is *** the resonance,the transitions of the states induce the energy called whispering gallery mode(WGM)at the circuit center,which is the squeezed *** generated electron oscillation within the WGM envelope oscillated by the frequency is known as the Rabi *** the successive filtering with continuous AC input via the selected port,the electron cloud warp speed can be generated and achieved inside the two-level *** constructed microstrip ring radius is 25 mm,and the experimental results of the Rabi antenna characteristics are in good agreement with the simulation *** obtained resonant antenna oscillation frequency is 2.103 *** electron cloud warp speed of 1.100c and time dilation of 0.006μs are obtained.

关键词： integrated photonics waveguide microwave photonics Rabi antenna

GLIAL ACTIVATION STATES DURING MPTP-INDUCED DOPAMINERGIC DEGENERATION

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IBRO Neuroscience Reports 2023年 15卷 S268-S268页

作者： Leyre Ayerra Miguel Angel Abellanas Leyre Basurco Adriana Tavira Esther Luquin Amaya Vilas Ibon Tamayo Mikel Hernaez Pedro Clavero Elisa Mengual Sandra Hervás-Stubbs Maria S. Aymerich CIMA Neuroscience Program Pamplona (Navarra) Spain Universidad de Navarra Department Of Biochemistry And Genetics Science School Pamplona (Navarra) Spain Universidad de Navarra Pathology Anatomy And Physiology Department Medical School Pamplona (Navarra) Spain CIMA Oncohematology Program Pamplona (Navarra) Spain CIMA Computational Biology Program Pamplona (Navarra) Spain Hospital Center of Navarra Neurology Service Pamplona (Navarra) Spain CIMA Immunology Program Pamplona (Navarra) Spain