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Increased throughput in methods for simulating protein ligand binding and unbinding 提高模拟蛋白质配体结合和解除结合方法的处理量。
IF 6.1 2区 生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-06-25 DOI: 10.1016/j.sbi.2024.102871
Syeda Rehana Zia , Adriana Coricello , Giovanni Bottegoni

By incorporating full flexibility and enabling the quantification of crucial parameters such as binding free energies and residence times, methods for investigating protein-ligand binding and unbinding via molecular dynamics provide details on the involved mechanisms at the molecular level. While these advancements hold promise for impacting drug discovery, a notable drawback persists: their relatively time-consuming nature limits throughput. Herein, we survey recent implementations which, employing a blend of enhanced sampling techniques, a clever choice of collective variables, and often machine learning, strive to enhance the efficiency of new and previously reported methods without compromising accuracy. Particularly noteworthy is the validation of these methods that was often performed on systems mirroring real-world drug discovery scenarios.

通过分子动力学研究蛋白质与配体的结合和解除结合的方法具有充分的灵活性,并能对结合自由能和停留时间等关键参数进行量化,从而提供分子水平上相关机制的详细信息。虽然这些进步有望影响药物发现,但一个显著的缺点依然存在:它们相对耗时的特性限制了通量。在此,我们将对最近的实现方法进行调查,这些方法采用了增强型采样技术、集体变量的巧妙选择以及机器学习等综合方法,力求在不影响准确性的前提下提高新方法和以前报道过的方法的效率。尤其值得注意的是,这些方法通常在反映真实世界药物发现场景的系统上进行验证。
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引用次数: 0
Quantum mechanical-based strategies in drug discovery: Finding the pace to new challenges in drug design 基于量子力学的药物发现策略:找到应对药物设计新挑战的步伐
IF 6.1 2区 生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-06-23 DOI: 10.1016/j.sbi.2024.102870
Tiziana Ginex , Javier Vázquez , Carolina Estarellas , F.Javier Luque

The expansion of the chemical space to tangible libraries containing billions of synthesizable molecules opens exciting opportunities for drug discovery, but also challenges the power of computer-aided drug design to prioritize the best candidates. This directly hits quantum mechanics (QM) methods, which provide chemically accurate properties, but subject to small-sized systems. Preserving accuracy while optimizing the computational cost is at the heart of many efforts to develop high-quality, efficient QM-based strategies, reflected in refined algorithms and computational approaches. The design of QM-tailored physics-based force fields and the coupling of QM with machine learning, in conjunction with the computing performance of supercomputing resources, will enhance the ability to use these methods in drug discovery. The challenge is formidable, but we will undoubtedly see impressive advances that will define a new era.

化学空间扩展到包含数十亿可合成分子的有形库,为药物发现带来了令人兴奋的机遇,但同时也对计算机辅助药物设计优先选择最佳候选药物的能力提出了挑战。这直接冲击了量子力学(QM)方法,该方法可提供精确的化学特性,但受制于小尺寸系统。在优化计算成本的同时保持准确性,是许多人努力开发基于量子力学的高质量、高效策略的核心,这体现在完善的算法和计算方法上。设计基于QM的物理力场以及将QM与机器学习结合起来,再加上超级计算资源的计算性能,将提高在药物发现中使用这些方法的能力。挑战是艰巨的,但我们无疑会看到令人印象深刻的进步,这将定义一个新的时代。
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引用次数: 0
Long non-coding RNAs in the nucleolus: Biogenesis, regulation, and function 核仁中的长非编码 RNA:生物发生、调控和功能
IF 6.1 2区 生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-06-22 DOI: 10.1016/j.sbi.2024.102866
Shuo Han , Ling-Ling Chen

The nucleolus functions as a multi-layered regulatory hub for ribosomal RNA (rRNA) biogenesis and ribosome assembly. Long noncoding RNAs (lncRNAs) in the nucleolus, originated from transcription by different RNA polymerases, have emerged as critical players in not only fine-tuning rRNA transcription and processing, but also shaping the organization of the multi-phase nucleolar condensate. Here, we review the diverse molecular mechanisms by which functional lncRNAs operate in the nucleolus, as well as their profound implications in a variety of biological processes. We also highlight the development of emerging molecular tools for characterizing and manipulating RNA function in living cells, and how application of such tools in the nucleolus might enable the discovery of additional insights and potential therapeutic strategies.

核仁是核糖体 RNA(rRNA)生物发生和核糖体组装的多层调控枢纽。核仁中的长非编码 RNA(lncRNA)由不同的 RNA 聚合酶转录而来,已成为不仅微调 rRNA 转录和加工,而且塑造多相核仁凝聚物组织的关键角色。在这里,我们回顾了功能性 lncRNA 在核仁中运作的各种分子机制,以及它们在各种生物过程中的深远影响。我们还重点介绍了用于表征和操纵活细胞中 RNA 功能的新兴分子工具的发展,以及在核仁中应用这些工具如何能够发现更多的见解和潜在的治疗策略。
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引用次数: 0
Molecular models of bidirectional promoter regulation 双向启动子调控的分子模型
IF 6.1 2区 生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-06-20 DOI: 10.1016/j.sbi.2024.102865
Sarah Nemsick , Anders S. Hansen

Approximately 11% of human genes are transcribed by a bidirectional promoter (BDP), defined as two genes with <1 kb between their transcription start sites. Despite their evolutionary conservation and enrichment for housekeeping genes and oncogenes, the regulatory role of BDPs remains unclear. BDPs have been suggested to facilitate gene coregulation and/or decrease expression noise. This review discusses these potential regulatory functions through the context of six prospective underlying mechanistic models: a single nucleosome free region, shared transcription factor/regulator binding, cooperative negative supercoiling, bimodal histone marks, joint activation by enhancer(s), and RNA-mediated recruitment of regulators. These molecular mechanisms may act independently and/or cooperatively to facilitate the coregulation and/or decreased expression noise predicted of BDPs.

大约 11% 的人类基因是由双向启动子(BDP)转录的,双向启动子是指两个基因的转录起始位点之间有 1 kb 的距离。尽管双向启动子在进化过程中保持不变,而且富含看家基因和癌基因,但其调控作用仍不清楚。有人认为 BDPs 可促进基因核心调控和/或降低表达噪音。本综述通过以下六种潜在的基本机制模型来讨论这些潜在的调控功能:单个无核糖体区域、共享转录因子/调控因子结合、合作性负超螺旋、双模组蛋白标记、增强子联合激活以及 RNA 介导的调控因子招募。这些分子机制可能独立和/或合作发挥作用,促进核心调控和/或降低预测的 BDPs 表达噪音。
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引用次数: 0
Cryo-focused ion beam for in situ structural biology: State of the art, challenges, and perspectives 用于原位结构生物学的低温聚焦离子束:技术现状、挑战和前景
IF 6.8 2区 生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-06-19 DOI: 10.1016/j.sbi.2024.102864
Alex J. Noble, Alex de Marco

Cryogenic-focused ion beam (cryo-FIB) instruments became essential for high-resolution imaging in cryo-preserved cells and tissues. Cryo-FIBs use accelerated ions to thin samples that would otherwise be too thick for cryo-electron microscopy (cryo-EM). This allows visualizing cellular ultrastructures in near-native frozen hydrated states. This review describes the current state-of-the-art capabilities of cryo-FIB technology and its applications in structural cell and tissue biology. We discuss recent advances in instrumentation, imaging modalities, automation, sample preparation protocols, and targeting techniques. We outline remaining challenges and future directions to make cryo-FIB more precise, enable higher throughput, and be widely accessible. Further improvements in targeting, efficiency, robust sample preparation, emerging ion sources, automation, and downstream electron tomography have the potential to reveal intricate molecular architectures across length scales inside cells and tissues. Cryo-FIB is poised to become an indispensable tool for preparing native biological systems in situ for high-resolution 3D structural analysis.

低温聚焦离子束(Cryo-FIB)仪器对于低温保存的细胞和组织的高分辨率成像至关重要。低温聚焦离子束利用加速离子来稀释样本,否则样本太厚就无法进行低温电子显微镜(cryo-EM)成像。这样就可以观察到近原生冷冻水合状态下的细胞超微结构。本综述介绍了冷冻-FIB 技术的当前最新能力及其在细胞和组织结构生物学中的应用。我们讨论了仪器、成像模式、自动化、样品制备方案和靶向技术方面的最新进展。我们概述了要使冷冻-FIB 技术更加精确、实现更高通量和广泛应用所面临的挑战和未来发展方向。在靶向、效率、稳健的样品制备、新兴离子源、自动化和下游电子断层扫描方面的进一步改进有可能揭示细胞和组织内部跨长度尺度的复杂分子结构。Cryo-FIB 将成为原位制备本地生物系统以进行高分辨率三维结构分析的不可或缺的工具。
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引用次数: 0
Advances in cryo-ET data processing: meeting the demands of visual proteomics 低温电子显微镜数据处理的进展:满足视觉蛋白质组学的需求。
IF 6.8 2区 生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-06-17 DOI: 10.1016/j.sbi.2024.102861
Abigail J.I. Watson , Alberto Bartesaghi

Cryogenic electron tomography (cryo-ET), a method that enables the viewing of biomolecules in near-native environments at high resolution, is rising in accessibility and applicability. Over the past several years, once slow sample preparation and data collection procedures have seen innovations which enable rapid collection of the large datasets required for attaining high resolution structures. Increased data availability has provided a driving force for exciting improvements in cryo-ET data processing methodologies throughout the entire processing pipeline and the development of accessible graphical user interfaces (GUIs) that enable individuals inexperienced in computational fields to convert raw tilt series into 3D structures. These advances in data processing are enabling cryo-ET to attain higher resolution and extending its applicability to more complex samples.

低温电子断层扫描(cryo-ET)是一种能够在近原生环境中以高分辨率观察生物分子的方法,其可获得性和适用性正在不断提高。在过去的几年中,曾经缓慢的样品制备和数据收集程序有了创新,能够快速收集获得高分辨率结构所需的大量数据集。数据可用性的提高推动了整个处理流程中低温电子显微镜数据处理方法的重大改进,也推动了图形用户界面(GUI)的发展,使缺乏计算领域经验的人也能将原始倾斜序列转换成三维结构。数据处理方面的这些进步使低温电子显微镜能够达到更高的分辨率,并将其适用范围扩展到更复杂的样本。
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引用次数: 0
Nuclear periphery and its mechanical regulation in cell fate transitions 细胞命运转换中的核外围及其机械调控
IF 6.8 2区 生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-06-17 DOI: 10.1016/j.sbi.2024.102867
Rebecca K. Stephens, Yekaterina A. Miroshnikova

Cell fate changes require rewiring of transcriptional programs to generate functionally specialized cell states. Reconfiguration of transcriptional networks requires overcoming epigenetic barriers imposed by silenced heterochromatin in order to activate lineage-specific genes. Further, cell fate decisions are made in a tissue-specific context, where cells are physically linked to each other as well as to the connective tissue environment. Here, cells are continuously exposed to a multitude of mechanical forces emanating from cellular dynamics in their local microenvironments, for example through cell movements, cell divisions, tissue contractions, or fluid flow. Through their ability to deform cellular structures and activate receptors, mechanical forces can be sensed at the plasma membrane, but also at the nuclear periphery through direct or cytoskeleton-mediated deformation of the nuclear envelope. This deformation and the associated signaling is capable of triggering changes in the mechanical state of the nuclear membranes, the organization and rigidity of the underlying nuclear lamina, compaction state of chromatin, and ultimately transcription. This review focuses on the role of nuclear architecture, particularly the nuclear lamina-chromatin interface, and its mechanical regulation in cell fate decisions as well as its physiological role in development and cellular reprogramming.

细胞命运的改变需要转录程序的重新布线,以产生功能特化的细胞状态。转录网络的重新配置需要克服沉默的异染色质所造成的表观遗传学障碍,以激活特定世系的基因。此外,细胞命运的决定是在组织特异性的背景下做出的,细胞之间以及细胞与结缔组织环境之间都存在物理联系。在这种情况下,细胞会不断受到来自其局部微环境中细胞动态的多种机械力的影响,例如通过细胞运动、细胞分裂、组织收缩或液体流动产生的机械力。机械力不仅能使细胞结构变形并激活受体,还能通过核膜的直接变形或细胞骨架介导的变形在细胞核外围感知到机械力。这种变形和相关信号能够引发核膜的机械状态、底层核薄层的组织和刚性、染色质的压实状态以及最终转录的变化。这篇综述将重点探讨核结构(尤其是核薄层-染色质界面)的作用及其在细胞命运决定中的机械调控,以及它在发育和细胞重编程中的生理作用。
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引用次数: 0
Single-molecule fluorescence imaging of DNA maintenance protein binding dynamics and activities on extended DNA 扩展 DNA 上 DNA 维护蛋白结合动态和活动的单分子荧光成像
IF 6.8 2区 生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-06-15 DOI: 10.1016/j.sbi.2024.102863
Elizabeth Marie Irvin , Hong Wang

Defining the molecular mechanisms by which genome maintenance proteins dynamically associate with and process DNA is essential to understand the potential avenues by which these stabilizing mechanisms are disrupted. Single-molecule fluorescence imaging (SMFI) of protein dynamics on extended DNA has greatly expanded our ability to accomplish this, as it captures singular biomolecular interactions – in all their complexity and diversity – without relying on ensemble-averaging of bulk protein activity as most traditional biochemical techniques must do. In this review, we discuss how SMFI studies with extended DNA have substantially contributed to genome stability research over the past two years.

要了解这些稳定机制被破坏的潜在途径,就必须确定基因组维护蛋白与 DNA 动态关联和处理 DNA 的分子机制。对扩展 DNA 上蛋白质动态的单分子荧光成像(SMFI)极大地拓展了我们实现这一目标的能力,因为它能捕捉单个生物分子的相互作用--其复杂性和多样性--而不像大多数传统生化技术那样必须依赖于大量蛋白质活性的集合平均。在这篇综述中,我们将讨论在过去两年中,利用扩展 DNA 进行的 SMFI 研究是如何为基因组稳定性研究做出重大贡献的。
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引用次数: 0
DNA topology: A central dynamic coordinator in chromatin regulation DNA 拓扑学:染色质调控的核心动态协调器
IF 6.8 2区 生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-06-14 DOI: 10.1016/j.sbi.2024.102868
Shuai Li, Charan Vemuri, Chongyi Chen

Double helical DNA winds around nucleosomes, forming a beads-on-a-string array that further contributes to the formation of high-order chromatin structures. The regulatory components of the chromatin, interacting intricately with DNA, often exploit the topological tension inherent in the DNA molecule. Recent findings shed light on, and simultaneously complicate, the multifaceted roles of DNA topology (also known as DNA supercoiling) in various aspects of chromatin regulation. Different studies may emphasize the dynamics of DNA topological tension across different scales, interacting with diverse chromatin factors such as nucleosomes, nucleic acid motors that propel DNA-tracking processes, and DNA topoisomerases. In this review, we consolidate recent studies and establish connections between distinct scientific discoveries, advancing our current understanding of chromatin regulation mediated by the supercoiling tension of the double helix. Additionally, we explore the implications of DNA topology and DNA topoisomerases in human diseases, along with their potential applications in therapeutic interventions.

双螺旋 DNA 缠绕在核小体上,形成串珠阵列,进一步促进了高阶染色质结构的形成。染色质中的调控成分与 DNA 相互作用,经常利用 DNA 分子固有的拓扑张力。最近的发现揭示了 DNA 拓扑学(也称为 DNA 超卷曲)在染色质调控各方面的多方面作用,同时也使其变得更加复杂。不同的研究可能会强调 DNA 拓扑张力在不同尺度上的动态变化,并与核小体、推动 DNA 跟踪过程的核酸马达和 DNA 拓扑异构酶等多种染色质因子相互作用。在这篇综述中,我们整合了最近的研究,并在不同的科学发现之间建立了联系,从而推进了我们目前对由双螺旋超卷曲张力介导的染色质调控的理解。此外,我们还探讨了DNA拓扑学和DNA拓扑异构酶对人类疾病的影响,以及它们在治疗干预中的潜在应用。
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引用次数: 0
Editorial overview–Artificial intelligence methodologies in structural biology: Bridging the gap to medical applications 编辑综述-结构生物学中的人工智能方法:缩小医学应用差距
IF 6.8 2区 生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-06-12 DOI: 10.1016/j.sbi.2024.102862
Tero Aittokallio, Evandro Fei Fang
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引用次数: 0
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Current opinion in structural biology
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