Bulletin of the American Physical Society
APS March Meeting 2023
Volume 68, Number 3
Las Vegas, Nevada (March 5-10)
Virtual (March 20-22); Time Zone: Pacific Time
Session M08: DNA Mechanics and Gene Expression IIFocus
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Sponsoring Units: DBIO Chair: Sumitabha Brahmachari, Rice University Room: Room 131 |
Wednesday, March 8, 2023 8:00AM - 8:36AM |
M08.00001: Torsional Mechanics of Fundamental Processes Invited Speaker: Michelle D Wang |
Wednesday, March 8, 2023 8:36AM - 8:48AM |
M08.00002: Physical Mechanisms for DNA Twist Changes and Supercoiling Induced by Salt and Temperature Changes Liang Dai DNA double-helix structure deforms with salt change and temperature change, and such deformations can cause DNA supercoils and modify DNA-protein interactions, which affects DNA packaging and gene expression. Here, our magnetic tweezers experiments observed that the increase of salt concentration leads to substantial DNA overwinding. Our simulations and theoretical calculation quantitatively explain the salt-induced twist change through the mechanism: More salt enhances the screening of interstrand electrostatic repulsion and hence reduces DNA diameter, which is transduced to twist increase through twist-diameter coupling. We determined that the coupling constant is 4.5 ± 0.8 kBT/(degrees·nm) for one base pair. The coupling comes from the restraint of the contour length of DNA backbone. On the basis of this coupling constant and diameter-dependent DNA conformational entropy, we predict the temperature dependence of DNA twist per base pair as approximately −0.01 degree/°C, which agrees with our and previous experimental results. Our analysis suggests that twist-diameter coupling is a common driving force for salt- and temperature-induced DNA twist changes. |
Wednesday, March 8, 2023 8:48AM - 9:00AM |
M08.00003: Tensile force in a single-stranded DNA gap Harold D Kim We recently measured the melting (or dehybridization) rate of a short DNA duplex in the presence of small tensile forces in the range of 1-5 pN and found that the melting rate decays exponentially with force even in this small force range. Interestingly, we also observed that the dehybridization rate of a short oligo from a single-stranded DNA (ssDNA) gap is significantly faster than that from an isolated duplex. This result is consistent with the presence of ~1pN of tensile force in the ssDNA gap. We hypothesized that this tensile force arises from the steric repulsion between the double-stranded DNA (dsDNA) segments flanking the gap. We used a simple model to calculate the mutually excluded volume between two dsDNA segments as a function of distance, which produces a force of a similar magnitude. Coarse-grained simulations of our system also reveal a similar force of entropic origin. |
Wednesday, March 8, 2023 9:00AM - 9:12AM |
M08.00004: Detecting Poloidal Bias In DNA Minicircles Tony Lemos Bending of DNA over a few helical periods is anisotropic due to the helical nature of DNA (e.g., roll vs. twist and roll towards major groove vs. minor groove), and the degree of this anisotropy is expected to be DNA-sequence dependent. As a result, when DNA of about ten helical periods in length is covalently closed to form a minicircle, certain minor grooves may prefer facing inward to minimize the total bending energy of the minicircle. This alludes to a bias in the poloidal orientation of the minicircle. Such poloidal bias in the minicircle was seen in a recent molecular dynamics study, but has not been demonstrated experimentally. Here, we introduce a single-molecule fluorescence method to measure the poloidal bias in DNA minicircles. In this method, we exploit a DNA-binding protein, where its binding affinity depends on DNA curvature, and measure its binding kinetics to a series of DNA minicircles that contain a single binding site at different positions. Using the measured protein binding profile, we are able to confirm sequence-dependent poloidal bias of DNA minicircles predicted by a previous computational study. |
Wednesday, March 8, 2023 9:12AM - 9:24AM |
M08.00005: Stability of DNA double helix under sharp bending Jun Soo Kim Sharp DNA bending is essential in DNA structure and function inside the cell, and small DNA minicircles with <100 base pairs (bp) have been employed to mimic sharply bent DNA molecules. In this presentation, we report extensive molecular dynamics (MD) simulations of double-stranded DNA (dsDNA) minicircles with lengths between 64 and 106 bp, investigating the stability of the DNA double helix under various extents of DNA bending. We developed a quantitative definition of the kink, which is the local structural disruption, based on the lifetime of base-pair opening, and presents a diagram for kink formation in the parameter space of curvature and superhelical density, representing the extents of DNA bending and twisting, respectively. Our simulation results show that the DNA double helix endures sharp bending up to the curvature of 0.26 nm-1 (corresponding to the length of 76 bp) and the stability is sensitive to torsional stress by small over- and under-twisting under sharp DNA bending. The kink formation occurred only at the DNA minor groove facing inward, suggesting the role of the twist-bend coupling in stabilizing sharply bent DNA. |
Wednesday, March 8, 2023 9:24AM - 10:00AM |
M08.00006: Multiscale modeling of chromatin: from fibers to genes to chromosomes Invited Speaker: Tamar Schlick Digitizing the human genome and the genomes of many model organism has been a landmark achievement of modern science. However, deciphering thetertiary organization of DNA's folding in the cell, and hence accessibility to the cellular machinery, is essential for understanding how genetic information is replicated, transcribed, silenced, and edited in fundamental processes including gene expression, DNA replication and repair, cell division and differentiation, and cancer progression. To address this multiscale folding challenge, many computational approaches have been developed to complement experimental structure determination techniques. I will describe our coarse-grained mesoscale chromatin model and novel equilibrium and dynamics algorithms to sample higher-order chromatin structure as a function of internal and external parameters and fold genes from first principles, interpret folding mechanisms relevant to cell differentiation and cancer progression, and simulate chromatin conformations consistent from experimental chromosome conformation capture contact maps. The studies reveal intriguing hierarchical looping mechanisms in genes that may play a role in gene silencing, protein-driven transitions of chromatin condensation that play a role in human lymphoma, and how a combination of epigenetic factors regulates chromatin topologies on both local and global scales. |
Wednesday, March 8, 2023 10:00AM - 10:12AM |
M08.00007: Understanding Transcriptional Regulation by Characterizing Gene Regulatory Functions of Synthetic Loci in Mammalian Cells Zheng Diao, Oleg A Igoshin, Caleb J Bashor Gene expression is dynamically regulated by transcription factors (TFs) during development and in response to environmental signals. The relationship between TF concentration and gene expression is referred to as gene regulatory function (GRF). Mammalian GRFs integrate information from TF occupancy, epigenetic modifications and chromatin structure. A quantitative understanding of the underlying mechanisms regulating GRF is essential for understanding fundamental biological processes and achieving predictive control over gene expression. However, endogenous mammalian gene loci exhibit complex pleiotropic regulatory interactions that limit our ability to decouple underlying mechanisms governing their GRFs. To overcome this limit, we constructed a fully-composable synthetic reporter locus that enables single-cell fluorescent measurement of steady-state and dynamic transcriptional activities. By expressing fluorescently labeled synthetic TFs—individually or in combination—that regulate the locus, we can precisely quantify changes in transcription rate and noise. In addition, we identified combinations of regulatory mechanisms that synergistically regulate GRF. To understand the GRFs, we developed non-equilibrium theoretical models that allow us to make experimentally testable predictions. In the future, we envision using these experimental and theoretical approaches in tandem to establish quantitative rules for engineering complex gene networks in mammalian cells. |
Wednesday, March 8, 2023 10:12AM - 10:24AM |
M08.00008: A Differentiable Model of Nucleic Acid Dynamics Ryan Krueger, Megan C Engel, Michael P Brenner Writing molecular dynamics simulations in automatic differentiation libraries has recently emerged as a new paradigm for optimization over physical systems. While practitioners have developed proof-of-concepts for small systems, no biophysical force field complex enough to capture experimental dynamics has been implemented in this fashion. Here, we present an implementation of oxDNA, a popular force field for modelling nucleic acids, in JAX-MD, a state of the art differentiable molecular dynamics library. Using our framework, we reparameterize oxDNA from scratch using the structural, thermodynamic, and mechanical data originally used in its parameterization. Crucially, using automatic differentiation for biophysical modelling permits unprecedented model transparency and reproducibility; in particular, it enables straightforward (i) incorporation of new experimental data and (ii) custom reparameterization. We are also excited by the possibility our framework affords to optimize over sequences in service of inverse design. |
Wednesday, March 8, 2023 10:24AM - 10:36AM |
M08.00009: Structural and Dynamic signatures of active chromatin polymers Sumitabha Brahmachari, Tomer Markovich, Frederick C MacKintosh, Jose N Onuchic Maintenance of the chromatin structure is an active process since many ATP-consuming proteins are simultaneously applying forces at microscopic lengthscales. We model activity in coarse-grained chromatin as an additive persistent noise and explore the role of active forces in shaping the structure and dynamics of chromatin. We propose activity as an important force regulating genome structural characteristics, such as chromosome compaction and nuclear positioning. Importantly, this model predicts novel structural and dynamic regimes, and key experimentally testable signatures associated with activity, that otherwise may not be captured in an effective-equilibrium model. |
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