OpenABC Enables Flexible, Simplified, and Efficient GPU Accelerated Simulations of Biomolecular Condensates

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2023, Volume and Issue: unknown

Published: April 21, 2023

Biomolecular condensates are important structures in various cellular processes but challenging to study using traditional experimental techniques. In silico simulations with residue-level coarse-grained models strike a balance between computational efficiency and chemical accuracy. They could offer valuable insights by connecting the emergent properties of these complex systems molecular sequences. However, existing often lack easy-to-follow tutorials implemented software that is not optimal for condensate simulations. To address issues, we introduce OpenABC, package greatly simplifies setup execution multiple force fields Python scripting. OpenABC seamlessly integrates OpenMM dynamics engine, enabling efficient performances on single GPU rival speed achieved hundreds CPUs. We also provide tools convert configurations all-atom atomistic anticipate Open-ABC will significantly facilitate adoption broader community investigate structural dynamical condensates. available at https://github.com/ZhangGroup-MITChemistry/OpenABC.

Language: Английский

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Machine learning reveals the diversity of human 3D chromatin contact patterns

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2023, Volume and Issue: unknown

Published: Dec. 23, 2023

Abstract Understanding variation in chromatin contact patterns across human populations is critical for interpreting non-coding variants and their ultimate effects on gene expression phenotypes. However, experimental determination of contacts at a population-scale prohibitively expensive. To overcome this challenge, we develop validate machine learning method to quantify the diversity 3D 2 kilobase resolution from genome sequence alone. We then apply approach thousands diverse modern humans inferred human-archaic hominin ancestral genome. While divergence genome-wide are qualitatively similar divergence, find that local 1-megabase genomic windows does not follow divergence. In particular, identify 392 with significantly greater than expected sequence. Moreover, 26% have rare observed small number individuals. Using silico mutagenesis most changes do result contacts. However substantial just one or few can lead divergent without individuals carrying those having high summary, inferring maps reveals patterns. anticipate these genetically will provide reference future work function evolution populations.

Language: Английский

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Explicit Ion Modeling Predicts Physicochemical Interactions for Chromatin Organization

Published: Jan. 10, 2024

Molecular mechanisms that dictate chromatin organization in vivo are under active investigation, and the extent to which intrinsic interactions contribute this process remains debatable. A central quantity for evaluating their contribution is strength of nucleosome-nucleosome binding, previous experiments have estimated range from 2 14 k B T . We introduce an explicit ion model dramatically enhance accuracy residue-level coarse-grained modeling approaches across a wide ionic concentrations. This allows de novo predictions computationally efficient, enabling large-scale conformational sampling free energy calculations. It reproduces energetics protein-DNA binding unwinding single nucleosomal DNA, resolves differential impact mono divalent ions on conformations. Moreover, we showed can reconcile various quantifying interactions, providing explanation large discrepancy between existing estimations. predict interaction at physiological conditions be 9 , value nonetheless sensitive DNA linker length presence histones. Our study strongly supports physicochemical phase behavior aggregates inside nucleus.

Language: Английский

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OpenNucleome for high resolution nuclear structural and dynamical modeling

Published: July 1, 2024

The intricate structural organization of the human nucleus is fundamental to cellular function and gene regulation. Recent advancements in experimental techniques, including high-throughput sequencing microscopy, have provided valuable insights into nuclear organization. Computational modeling has played significant roles interpreting observations by reconstructing high-resolution ensembles uncovering principles. However, absence standardized tools poses challenges for furthering investigations. We present OpenNucleome—an open-source software designed conducting GPU-accelerated molecular dynamics simulations nucleus. OpenNucleome offers particle-based representations chromosomes at a resolution 100 KB, encompassing lamina, nucleoli, speckles. This furnishes highly accurate models architecture, affording means dynamic condensate formation, fusion, exploration non-equilibrium effects. applied uncover mechanisms driving emergence “fixed points” within nucleus—signifying genomic loci robustly anchored proximity specific bodies functional purposes. anchoring remains resilient even amidst fluctuations chromosome radial positions shapes individual cells. Our findings lend support zoning model that elucidates genome functionality. anticipate serve as tool investigations, streamlining mechanistic explorations enhancing interpretation observations.

Language: Английский

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Explicit Ion Modeling Predicts Physicochemical Interactions for Chromatin Organization

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2023, Volume and Issue: unknown

Published: May 18, 2023

Abstract Molecular mechanisms that dictate chromatin organization in vivo are under active investigation, and the extent to which intrinsic interactions contribute this process remains debatable. A central quantity for evaluating their contribution is strength of nucleosome-nucleosome binding, previous experiments have estimated range from 2 14 k B T . We introduce an explicit ion model dramatically enhance accuracy residue-level coarse-grained modeling approaches across a wide ionic concentrations. This allows de novo predictions computationally efficient, enabling large-scale conformational sampling free energy calculations. It reproduces energetics protein-DNA binding unwinding single nucleosomal DNA, resolves differential impact mono divalent ions on conformations. Moreover, we showed can reconcile various quantifying interactions, providing explanation large discrepancy between existing estimations. predict interaction at physiological conditions be 9 , value nonetheless sensitive DNA linker length presence histones. Our study strongly supports physicochemical phase behavior aggregates inside nucleus.

Language: Английский

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