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 Q08: Molecular Machines IIFocus
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Sponsoring Units: DBIO Chair: Jin Yu, University of California-Irvine Room: Room 131 |
Wednesday, March 8, 2023 3:00PM - 3:36PM |
Q08.00001: Millisecond Functional Dynamics of RNA Polymerases Elucidated by Markov State Models Invited Speaker: Xuhui Huang RNA polymerase II (Pol II) undergoes a series of conformational changes when actively transcribing genes. I will present our group’s work on constructing Markov State Models (MSMs) from molecular dynamics (MD) simulations to elucidate dynamics of these conformational changes, including forward translocation, backtracking, and pyrophosphate release. In particular, I will explain the molecular mechanisms for Pol II to maintain transcription fidelity. Pol II efficiently detects errors and backtracks. Using MSMs, we identified a critical threonine residue acting as the checkpoint for backtracking. Following backtracking, Pol II cleaves the backtracked mis-incorporated nucleotide. We found strikingly that while specific amino acid residues of Pol II are critical for backtracking, cleavage of the mis-incorporated nucleotide only requires the RNA nucleotide itself (i.e., phosphate oxygen of mis-incorporated nucleotide). Based combining computational and experimental work, we reveal how Pol II accomplishes the task to catalyze two distinct chemical reactions using a single active site in a coordinated fashion, which is longstanding question in transcription. In addition, I will present our recent work on developing Generalized Master Equation (GME) models that encodes the non-Markovian dynamics in a generally time-dependent memory kernel. We successfully applied GMEs to elucidate molecular mechanisms of DNA loading into a bacterial RNA polymerase complex via flexible loading gate (consisting of the clamp and β-lobe domain), a process occurs at millisecond. We further reveal the mechanism of an antibiotics targeting this bacterial RNA Polymerase. |
Wednesday, March 8, 2023 3:36PM - 3:48PM |
Q08.00002: Speed variations of bacterial replisomes Simone Pigolotti, Deepak Bhat, Samuel Hauf, Charles Plessy, Yohei Yokobayashi Replisomes are large protein complexes that replicate DNA with astounding accuracy and speed. I will present a theory that predicts the abundance of DNA fragments in an exponentially growing bacterial population from the dynamics of replisome. We apply this theory to infer the replisome dynamics in E.coli from measured patterns of DNA abundance. Our study reveals the temperature dependence of the replisome speed, and shows that the replisome speed presents wave-like variations along the E.coli genome. I will discuss possible causes and consequences of this phenomenon. |
Wednesday, March 8, 2023 3:48PM - 4:00PM |
Q08.00003: Bacterial replication initiation as precision control in biology Haochen Fu, Dongyang Li, Fangzhou Xiao, Suckjoon Jun Replication initiation in bacteria is one of the most precise physiological controls in biology. Curiously, E. coli produces more than one order of magnitude larger number of DnaA proteins than needed, the widely conserved master regulator proteins in bacteria. More than 90% of the DnaA proteins are titrated by 300 binding sites encoded in the chromosome known as the DnaA boxes. In this work, we demonstrate that the number of DnaA boxes is optimal for initiation noise reduction and far more effective than autoregulation of DnaA production. We developed several novel experimental methods to control the number of DnaA boxes. As we increase the number of DnaA boxes, initiation is delayed steadily. However, the initiation noise (measured by CV) shows a non-monotonic behavior with the minimum at the wild-type number. We propose a model based on the DnaA flux to explain our results. We further discuss general implications of our results for precision control in biology. |
Wednesday, March 8, 2023 4:00PM - 4:36PM |
Q08.00004: DBIO Thesis Prize Winner: Jonathon L. YulyElectron bifurcation and correlations in biological energy transduction Invited Speaker: Jonathon L Yuly Electron bifurcation is an energy transduction process found across the tree of life, including complex III of the electron transport chain. Electron bifurcation drives electrons thermodynamically uphill by leveraging the downhill motion of other electrons. In fact, electron bifurcation can be fully electrochemically reversible, so that energy transduction occurs with near perfect thermodynamic efficiency. Electron bifurcation is a chemically challenging process because productive electron transfers must compete with strongly driven short-circuiting events. For decades, the absence of these short-circuits was shrouded in mystery, and all attempts towards synthetic electron bifurcation failed. Recently, we predicted that a conserved free energy landscape naturally prevents these short-circuiting electron transfers by large Boltzmann weights against microstates that initiate short-circuit events. Remarkably, although Boltzmann weights qualitatively capture the impact of the landscape on the short-circuit turnover, mean field transport theories fail to capture the efficient energy transduction, and instead predict short-circuiting, implying that correlations between redox cofactors cannot be naïvely neglected. Upon further exploration, this seems general for all energy transducing systems: mean field transport theory cannot capture the efficient energy transduction observed in biology. Correlations seem necessary, but which ones? |
Wednesday, March 8, 2023 4:36PM - 4:48PM |
Q08.00005: A free-energy profile study of a bipedal single-stranded DNA nanowalker's walking gaits Too Hon Lin DNA nanowalker is a class of dynamic DNA nanotechnology that exploits toehold mediated strand displacement and branch migration for movement. Speed is a key performance indicator of a good walker, and its threshold is determined by the walker's gait. Here, we conducted a systematic free energy profile study on a 15nt long ssDNA nanowalker on a dsDNA track using oxDNA, a coarse-grained DNA model. We identified all possible gaits for a ssDNA nanowalker, namely cartwheel, flip, prance and hop. The free energy profile of these gaits are sampled and studied in detail. The rate for a forward step is also estimated from the first passage time theory. Overall, we found that the local binding geometry affects the walking rate of each gaits. For cartwheel and flip, elongating the track will help increase the dissociation rate and decrease the first contact rate. The dissociation and first contact rate for a downhill prance walker decreases significantly on a longer track. Strategies to optimize the walking rate should therefore consider the gait of the bipedal walker. |
Wednesday, March 8, 2023 4:48PM - 5:00PM |
Q08.00006: How do self-assembled virus-like particles break open to expose their cargo? Amelia W Paine, Camila Cersosimo, Vinothan N Manoharan Viral capsids perform the competing functions of protecting their genome from the environment and exposing it during infection of a host cell. Compared to the process of forming a protective capsid, which for many viruses occurs through self-assembly, the process of exposing the genome is less well studied. Because the assembled state is a free-energy minimum, viral capsids must take advantage of new chemical environments in their hosts to disrupt their intermolecular interactions and expose their interior. By measuring the rate of binding of fluorescent molecules to the viral RNA, we indirectly explore the effects of chemical environments on capsid integrity. I will discuss the results of these experiments and their interpretation in terms of structural changes such as breathing modes. |
Wednesday, March 8, 2023 5:00PM - 5:36PM |
Q08.00007: Speedy synthetic DNA motors are on a roll Invited Speaker: Khalid Salaita DNA-based machines that walk by converting chemical energy into controlled motion could be useful in applications such as next-generation sensors, drug-delivery platforms and biological computing. Despite their exquisite programmability, DNA-based walkers are challenging to work with because of their low fidelity and slow rates (∼1 nm min–1). It would be highly desirable to create synthetic motors that can start to approach the performance of biological motor proteins such as myosin and dynein. In this talk, I will describe the development of DNA-based machines that roll rather than walk, and consequently have a maximum speed and processivity that is three orders of magnitude greater than the maximum for conventional DNA motors. The motors are made from DNA-coated spherical particles that hybridize to a surface modified with complementary RNA; the motion is achieved through the addition of RNase H, which selectively hydrolyses the hybridized RNA but not single stranded RNA. This type of motion has been described as a burnt-bridge Brownian ratchet. The spherical motors can move in a self-avoiding manner, and anisotropic particles, such as dimerized or rod-shaped particles, can travel linearly (balistically) without a track or external force. Motors display speeds of ~microns per minute and millimeter processivity which is starting to approach the speed and processivity of biological motors. I will highlight our recent work integrating logic gate operations into the motors to control their stop and go motion. I will also show that the motors can be used to detect SARS-CoV-2 whole virions and single nucleotide polymorphisms (SNPs) by measuring particle displacement using a smartphone camera. This type of sensing is of interest because it is far-from-equilibrium and thus provides a new conceptual approach to chemical sensing that is based on mechanotransduction. Finally, I will show that this type of motion is highly generalizable, spanning cargo that range in size from 10 nm to 10’s of microns. |
Wednesday, March 8, 2023 5:36PM - 5:48PM |
Q08.00008: Mechanical Properties of BiP (Binding Immunoglobin Protein) Zahra Alavi Abstract: Immunoglobulin Binding Protein (BiP) is a chaperone and molecular motor belonging to |
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