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On structural transitions, thermodynamic equilibrium, and the phase diagram of DNA and RNA duplexes under torque and tension (vol 103, pg 16200, 2006)

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PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA 2007年第1期104卷 395-395页

作者： Wereszczynski, Jeff Andricioaei, Ioan Department of Chemistry Program in Biophysics and Center for Computational Medicine and Biology University of Michigan Ann Arbor MI 48109 USA.

A precise understanding of the flexibility of double stranded nucleic acidsand the nature of their deformed conformations induced by external forces is important for a widerange of biological processes including transcriptional regulation, supercoil and catenane removal,and site-specific recombination. We present, at atomic resolution, a simulation of the dynamicsinvolved in the transitions from B-DNA and A-RNA to Pauling (P) forms and to denatured states drivenby application of external torque and tension. We then calculate the free energy profile along a B-to P-transition coordinate and from it, compute a reversible pathway, i.e., an isotherm of tensionand torque pairs required to maintain P-DNA in equilibrium. The reversible isotherm maps correctlyonto a phase diagram derived from single molecule experiments, and yields values of elongation,twist, and twist-stretch coupling in agreement with measured values. We also show thatconfigurational entropy compensates significantly for the large electrostatic energy increase due tocloser-packed P backbones. A similar set of simulations applied to RNA are used to predict a novelstructure, P-RNA, with its associated free energy, equilibrium tension, torque and structuralparameters, and to assign the location, on the phase-diagram, of a putative force-torque-dependentRNA "triple point.".

关键词： molecular dynamics nucleic acid conformations Pauling model for DNA single-molecule manipulations MOLECULAR-DYNAMICS NUCLEIC-ACIDS B-DNA STRETCHED DNA FORCE-FIELD ENERGY DISTRIBUTIONS CONFORMATION SPECTROSCOPY PARTICLE

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The grand biological universe: A comprehensive geometric construction of genome space

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The Innovation 2025年

作者： Hongyu Yu Nan Sun Ruohan Ren Tao Zhou Mengcen Guan Leqi Zhao Stephen S.-T. Yau Department of Mathematical Sciences Tsinghua University Beijing 100084 China Beijing Institute of Mathematical Sciences and Applications (BIMSA) Beijing 100084 China Computational and Systems Biology Program Sloan Kettering Institute Memorial Sloan Kettering Cancer Center New York City NY 10065 USA Tri-Institutional Training Program in Computational Biology and Medicine Weill Cornell Medicine New York City NY 10065 USA

Analyzing the geometric relationships among genomic sequences from a mathematical perspective and revealing the laws hidden within these relationships is a crucial challenge in bioinformatics. The natural vector method constructs a genome space by extracting statistical moments of k-mers to illuminate the relationships among genomes. This approach highlights a fundamental law in biology known as the convex hull principle, which states that natural vectors corresponding to different types of biological sequences form distinct, non-overlapping convex hulls. Previous studies have validated this important principle across various datasets. However, they often focused on specific kingdoms and did not thoroughly analyze the significance of the dimensions required for the convex hull separation. In this study, we integrate all reliable sequences from different kingdoms to construct the grand biological universe, within which we comprehensively validate the multi-level convex hull principle. We demonstrate that the separation of convex hulls arises from biological properties rather than mathematical characteristics of high-dimensional spaces. Furthermore, we develop suitable metrics within the grand biological universe to facilitate efficient sequence classification. This research advances the convex hull principle through both theoretical development and experimental validation, making significant contributions to the understanding of the geometric structure of genome space.

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Identification of novel TMEM16A blockers through integrated virtual screening, molecular dynamics, and experimental studies

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Scientific Reports 2025年第1期15卷 1-11页

作者： Sangkhawasi, Mattanun Pitaktrakul, Wichuda Khumjiang, Rungtiwa Shigeta, Yasuteru Muanprasat, Chatchai Hengphasatporn, Kowit Rungrotmongkol, Thanyada Center of Excellence in Biocatalyst and Sustainable Biotechnology Department of Biochemistry Faculty of Science Chulalongkorn University Bangkok 10330 Thailand Chakri Naruebodindra Medical Institute Faculty of Medicine Ramathibodi Hospital Mahidol University Bang Pla Bang Pli Samut Prakan 10540 Thailand Center for Computational Sciences University of Tsukuba 1-1-1 Tennodai Ibaraki Tsukuba 305-8577 Japan Program in Bioinformatics and Computational Biology Graduate School Chulalongkorn University Bangkok 10330 Thailand Division of Biochemistry Department of Preclinical Science Faculty of Medicine Thammasat University Pathumthani 12120 Thailand

The calcium-activated chloride channel TMEM16A is a promising drug target for treating hypertension, secretory diarrheas, and various cancers, including head and neck cancer. Despite its potential, no FDA-approved drugs have provided the structural basis for directly inhibiting TMEM16A. This study aims to identify a novel pore-blocker of TMEM16A by integrating virtual screening, molecular dynamics simulations, and in vitro studies. Using the calcium-bound structure of TMEM16A with and without the pore-blocker 1PBC, we performed virtual screening on nearly 90,000 compounds from the ChemDiv database. Approximately 67% of these compounds demonstrated better binding affinity than 1PBC. Among the top 20 compounds selected for short-circuit current assays using human lung adenocarcinoma cells (Calu-3), compounds N066-0059, N066-0060, and N066-0067 inhibited TMEM16A activity with IC₅₀ values of 0.24 µM, 0.41 µM, and 0.48 µM, respectively, which was lower than that of a positive control Ani9 (9 µM). Due to its highest potency in electrophysiological assays, N066-0059 was subjected to mechanistic studies. Molecular dynamics simulations elucidated its binding stability and strength, showing superior performance to 1PBC over 500 ns with 3 replicates. This study advances TMEM16A-targeted drug development, offering new insights for anticancer therapies. © The Author(s) 2025.

关键词： And electrophysiological assays Cytotoxicity Molecular dynamics Pore-blocker inhibitor TMEM16A Virtual screening

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BPS2025 - Mechanism-based modeling of drug-resistant mutations in cancer

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Biophysical Journal 2025年第3期124卷 505a-505a页

作者： Sukrit Singh John D. Chodera Markus Seeliger Computational and Systems Biology Program Memorial Sloan Kettering Cancer Center New York NY USA State University of New York Stony Brook Stony Brook NY USA

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A web-based histology atlas for the freshwater sentinel species Daphnia magna

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Science of the Total Environment 2025年 958卷 177930页

作者： Ngu, Mee S. Vanselow, Daniel J. Zaino, Carolyn R. Lin, Alex Y. Copper, Jean E. Beaton, Margaret J. Orsini, Luisa Colbourne, John K. Cheng, Keith C. Ang, Khai C. Department of Pathology Pennsylvania State University College of Medicine PA United States Jake Gittlen Laboratories for Cancer Research Pennsylvania State University College of Medicine PA United States Department of Biology Mount Allison University Sackville Canada Centre for Environmental Research and Justice The University of Birmingham Birmingham United Kingdom Institute for Computational and Data Sciences Pennsylvania State University State CollegePA United States Molecular and Precision Medicine Program Pennsylvania State University College of Medicine HersheyPA United States

Daphnia are keystone species of freshwater habitats used as model organisms in ecology and evolutionary biology. Their small size, wide geographic distribution, and sensitivity to chemicals make them useful as environmental sentinels in regulatory toxicology and chemical risk assessment. Biomolecular (-omic) assessments of responses to chemical toxicity, which reveal detailed molecular signatures, become more powerful when correlated with other phenotypic outcomes (such as behavioral, physiological, or histopathological) for comparative validation and regulatory relevance. However, the lack of histopathology or tissue phenotype characterization of this species presently limits our ability to assess cellular mechanisms of toxicity. Here, we address the central concept that interpreting aberrant tissue phenotypes requires a basic understanding of species normal microanatomy. We introduce the female and male Daphnia Histology Reference Atlas (DaHRA) for the baseline knowledge of Daphnia magna microanatomy. We also include developmental stages of female D. magna in the atlas. This interactive web-based resource of adult D. magna features overlaid vectorized demarcation of anatomical structures whose labels comply with an anatomical ontology created for this atlas. We demonstrate the potential utility of DaHRA for toxicological investigations by presenting aberrant phenotypes of acetaminophen-exposed D. magna. We envision DaHRA to facilitate the future integration of molecular and phenotypic data from the scientific community as we seek to understand how genes, chemicals, and environment interactions determine organismal phenotype. © 2024 The Authors

关键词： Biotic

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Insights into the binding interactions of Macitentan to bovine serum Albumin: A Spectroscopic, electrochemical and computational study

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Journal of Molecular Liquids 2025年 429卷

作者： Sadak, Selenay Dindar, Çiğdem Kanbeş Kabir, Md.Zahirul Rehman, Fazal Mohamad, Saharuddin B. Yildirim, Sercan Uslu, Bengi Ankara University Faculty of Pharmacy Department of Analytical Chemistry Ankara06560 Turkey Ankara University The Graduate School of Health Sciences Ankara06110 Turkey Biochemistry Program Institute of Biological Sciences Faculty of Science University Malaya Kuala Lumpur Malaysia Faculty of Science Bioinformatics Programme Institute of Biological Sciences Malaysia Centre of Research for Computational Sciences and Informatics for Biology Bioindustry Environment Agriculture and Healthcare University of Malaya Kuala Lumpur Malaysia Karadeniz Technical University Faculty of Pharmacy Department of Analytical Chemistry Trabzon Turkey

Macitentan (MACI) is an endothelial receptor antagonist used to treat pulmonary arterial hypertension (PAH). The pharmacokinetics and therapeutic efficacy of MACI are significantly influenced by its interaction with plasma proteins, especially bovine serum albumin (BSA). In this study, spectroscopic (fluorescence and UV–visible absorption spectroscopy), electrochemical, and computational techniques were applied to explore the binding properties and interaction mechanisms between MACI and BSA. The results indicated that the MACI quenched BSA fluorescence through a static mechanism. The interaction possessed a moderate binding affinity with Ka values ranging from 1.27 × 104 to 7.25 × 104 M−1 at different temperatures. Hydrophobic forces and hydrogen bonds were identified as critical factors in stabilizing the complex based on thermodynamic parameters. The local environment of tryptophan residues in BSA was found to be altered following the addition of MACI, as revealed by synchronous and three-dimensional fluorescence spectra. The spectroscopic studies were supported by electrochemical analyses, which indicated the formation of an electro-inactive complex between MACI and BSA. From the molecular docking experiments, the most likely binding site for MACI was found to be site I of BSA. Several hydrogen bonds and hydrophobic contacts were observed during the interaction of MACI with site I of BSA. These findings provided detailed insight to understand the binding properties of MACI to BSA, which may be beneficial for medical and pharmaceutical applications in the future. © 2025 Elsevier B.V.

关键词： Hydrogen bonds

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A MOLECULAR MECHANISM FOR Q(E)-QUENCHING

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FEBS LETTERS 1994年第3期352卷 265-270页

作者： CROFTS, AR YERKES, CT Program in Biophysics and Computational Biology University of Illinois 156 Davenport Hall 607 S. Mathews Urbana IL 61801 USA

We discuss energy-dependent fluorescence lowering (q(E)-quenching), and suggest a model to explain the experimental data currently available. The main elements of the model are: (a) the q(E)-quenching reflects a mechanism associated with a component of the light-harvesting antenna rather than the reaction center of photosystem (PS) II - we suggest that it occurs through formation of an efficient quencher in one of the minor chlorophyll protein (CP) complexes;(b) the minor CPs have glutamate residues instead of glutamines at positions shown in light-harvesting complex II (LHCII) to be ligands to chlorophylls near the lumenal interface. We suggest that the quenching reflects a change in ligation of chlorophyll on protonation of these glutamate residues leading to formation of an exciton coupled dimer with a neighboring pigment, in which additional energy levels allow vibrational relaxation of the excited singlet. The model accounts for the dependence on low lumenal pH, the ligand residue changes between LHCII and the minor CPs, the preferential distribution of components of the xanthophyll cycle in the minor CPs, the inhibition of q(E)-quenching by DCCD, and the specific binding of DCCD to the minor CPs.

关键词： Q(E)-QUENCHING LIGHT-HARVESTING COMPLEX CHLOROPHYLLS MOLECULAR MECHANISM PHOTOSYNTHESIS

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Cell cycle execution point analysis of ORC function and characterization of the checkpoint response to ORC inactivation in Saccharomyces cerevisiae (vol 11, pg 557, 2006)

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GENES TO CELLS 2006年第8期11卷 969-969页

作者： Gibson, Daniel G. Bell, Stephen P. Aparicio, Oscar M. Molecular and Computational Biology Program Department of Biological Sciences University of Southern California Los Angeles California 90089-2910 USA.

Chromosomal replication initiates through the assembly of a prereplicativecomplex (pre-RC) at individual replication origins in the G1-phase, followed by activation of thesecomplexes in the S-phase. In Saccharomyces cerevisiae, the origin recognition complex (ORC) bindsreplication origins throughout the cell cycle and participates in pre-RC assembly. Whether the ORCplays an additional role subsequent to pre-RC assembly in replication initiation or any otheressential cell cycle process is not clear. To study the function of the ORC during defined cellcycle periods, we performed cell cycle execution point analyses with strains containing aconditional mutation in the ORC1, ORC2 or ORC5 subunit of ORC. We found that the ORC is essentialfor replication initiation, but is dispensable for replication elongation or later cell cycleevents. Defective initiation in ORC mutant cells results in incomplete replication and mitoticarrest enforced by the DNA damage and spindle assembly checkpoint pathways. The involvement of thespindle assembly checkpoint implies a defect in kinetochore-spindle attachment or sister chromatidcohesion due to incomplete replication and/or DNA damage. Remarkably, under semipermissiveconditions for ORC1 function, the spindle checkpoint alone suffices to block proliferation,suggesting this checkpoint is highly sensitive to replication initiation defects. We discuss thepotential significance of these overlapping checkpoints and the impact of our findings on previouslypostulated role(s) of ORCs in other cell cycle functions.

关键词： replication Cell Cycle AOD use initiation physiological aspects Saccharomyces cerevisiae

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Modeling stochastic noise in gene regulatory systems

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Frontiers of Electrical and Electronic Engineering in China 2014年第1期9卷 1-29页

作者： Arwen Meister Chao Du Ye Henry Li Wing Hung Wong Computational Biology Lab Bio-X Program Stanford University Stanford CA 94305 USA

The Master equation is considered the gold standard for modeling the stochastic mechanisms of gene regulation in molecular detail, but it is too complex to solve exactly in most cases, so approximation and simulation methods are essential. However, there is still a lack of consensus about the best way to carry these out. To help clarify the situation, we review Master equation models of gene regulation, theoretical approximations based on an expansion method due to N.G. van Kampen and R. Kubo, and simulation algorithms due to D.T. Gillespie and P. Langevin. Expansion of the Master equation shows that for systems with a single stable steady-state, the stochastic model reduces to a deterministic model in a first-order approximation. Additional theory, also due to van Kampen, describes the asymptotic behavior of multistable systems. To support and illustrate the theory and provide further insight into the complex behavior of multistable systems, we perform a detailed simulation study comparing the various approximation and simulation methods applied to synthetic gene regulatory systems with various qualitative characteristics. The simulation studies show that for large stochastic systems with a single steady-state, deterministic models are quite accurate, since the probability distribution of the solution has a single peak tracking the deterministic trajectory whose variance is inversely proportional to the system size. In multistable stochastic systems, large fluctuations can cause individual trajectories to escape from the domain of attraction of one steady-state and be attracted to another, so the system eventually reaches a multimodal probability distribution in which all stable steady- states are represented proportional to their relative stability. However, since the escape time scales exponentially with system size, this process can take a very long time in large systems.

关键词： gene regulation stochastic modeling simulation Master equation Gillespie algorithm Langevin equation

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Applications of probability and statistics in cancer genomics

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Quantitative biology 2020年第2期8卷 95-108页

作者： Xiaotu Ma Sasi Arunachalam Yanling Liu Department of Computational Biology and Cancer Biology ProgramComprehensive Cancer CenterSt Jude Children's Research HospitalMemphisTN 38105USA

Background:The past decade has witnessed a rapid progress in our understanding of the genetics of cancer and its *** and statistical modeling played a pivotal role in the discovery of general patterns from cancer genomics datasets and continue to be of central importance for personalized ***:In this review we introduce cancer genomics from a probabilistic and statistical *** start from(1)functional classification of genes into oncogenes and tumor suppressor genes,then(2)demonstrate the importance of comprehensive analysis of different mutation types for individual cancer genomes,followed by(3)tumor purity analysis,which in turn leads to(4)the concept of ploidy and clonality,that is next connected to(5)tumor evolution under treatment pressure,which yields insights into cancer drug *** also discuss future challenges including the non-coding genomic regions,integrative analysis of genomics and epigenomics,as well as early cancer ***:We believe probabilistic and statistical modeling will continue to play important roles for novel discoveries in the field o f cancer genomics and personalized medicine.

关键词： cancer genomics sequence analysis probability and statistics

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