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 AA09: V: Molecular BiophysicsFocus
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Sponsoring Units: DBIO Chair: Aniket Bhattacharya, University of Central Florida Room: Virtual Room 9 |
Monday, March 20, 2023 5:00AM - 5:12AM |
AA09.00001: Following the binding and dissociation kinetics of unlabeled transcription factors at the single molecule level Ariel Kaplan Already from the seminal work of Jacob and Monod, a central regulatory role was recognized for the equilibrium occupancy of response elements by transcription factors (TFs), which depends on their concentration, affinity, and, in eukaryotes, the chromatin accessibility of their binding sites. However, recent studies have highlighted the importance of transient TF–DNA interactions, and indicate that the kinetics of TF binding and dissociation play an important role in regulating transcription in vivo. Their characterization requires measuring the full distribution of binding and dissociation times in a well-controlled assay. Here, we present a single-molecule optical-tweezers assay that exploits the thermal fluctuations of a DNA hairpin to detect the association and dissociation of individual, unlabeled transcription factors. We demonstrate this new approach by following the binding of Egr1 to its consensus motif and the three binding sites found in the promoter of the Lhb gene, and find that both association and dissociation are modulated by the 9 bp core motif and the sequences around it. In addition, CpG methylation modulates the dissociation kinetics in a sequence and position-dependent manner, which can both stabilize or destabilize the complex. Together, our findings show how variations in sequence and methylation patterns synergistically extend the spectrum of a protein’s binding properties, and demonstrate how the proposed approach can provide new insights into the function of transcription factors. |
Monday, March 20, 2023 5:12AM - 5:24AM |
AA09.00002: Importance of Many Body Interactions in DNA Synthesis Initiation G. Andrés A Cisneros The synthesis of DNA primers, which are subsequently extended, is performed by DNA primases. This process is indispensable for DNA replication, and thus the understanding of the precise mechanism for this process is of great importance. In this contribution we will present the molecular basis for the primase synthesis mechanism of the CRISPR-associated primase-polymerase from Marinitoga piezophila (Mp). The crystal structure of a primer initiation complex reveals how the incoming nucleotides are positioned within the active site, adjacent to metal cofactors and paired with the templating single-stranded DNA strand, before synthesis of the first phosphodiester bond. Quantum mechanical energy decomposition analysis was used to reveal the inter-molecular interactions between different components of the active site to understand the basis of the stabilization of the two triphosphate nucleotides in the active site prior to phosphodiester bond formation. Polarizable molecular dynamics simulations provide additional insights on the stability of the enzyme/substrate complex. Results from these calculations and relevance of many-body effects in the stabilization of the system will be discussed. |
Monday, March 20, 2023 5:24AM - 5:36AM |
AA09.00003: Investigating recognition and sequence preference of Kaiso interactions with methylated DNA Bidhya Thapa, Narayan P Adhikari, Purushottam TIwari, Prem P Chapagain
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Monday, March 20, 2023 5:36AM - 5:48AM |
AA09.00004: Amino acid characteristics in protein native state structures Tatjana Škrbic, Achille Giacometti, Amos Maritan, Trinh X Hoang, Jayanth R Banavar Proteins are chain molecules made up of twenty naturally occuring amino acid types. The set of amino acid side chains span a range of geometrical shapes, physical sizes, as well as chemical properties. We analyze experimental data on amino acid identity and side chain orientations with respect to the protein backbone in more than 4000 high-resolution protein native state structures. We consider the magnitude and direction of protrusion along with a simplified chemical attribute captured by a hydrophobic scale. The geometrical, physical, and chemical properties of the side chains are simultaneously studied using principal component analysis to infer the consensus propensity to harmoniously substitute one amino acid with another in protein sequences, while preserving the native state structure. This propensity also indicates the destabilization potential of a point mutation to the native state fold. We benchmark our results against mutational studies reported in the literature. |
Monday, March 20, 2023 5:48AM - 6:00AM |
AA09.00005: Computational Analysis of the Effects of the Early Effects of Disulfide Bonds Cleavage on the Structure of Human Serum Albumin Kiara Fenner Traditional structural biology methods have employed diffractive techniques (such as x-ray diffraction and cryo-electron microscopy, cryo-EM) or nuclear magnetic resonance (NMR) to retrieve the 3-dimensional atomistic structure of biomolecules. The high resolution of these experimental techniques, bring an important set of experimental challenges including sample preparation and operating under extreme non-physiological conditions. In addition, these techniques mostly deny much of the dynamics of biomolecules which are deemed to be essential for their functions. |
Monday, March 20, 2023 6:00AM - 6:12AM |
AA09.00006: Mode projected dynamics of globular and membrane proteins Saravana Prakash Thirumuruganandham In this work, we performed simulations of opsin as a model membrane protein and ovalbumin using CHARMM35b2 to understand the projected mode dynamics, which is useful to analyze intramolecular energy transfer in proteins. We projected the few selective low-frequency normal modes into the molecular dynamics trajectories of opsin in solvent and vacuum. The hydration effect of normal modes in proteins was evaluated.To calculate the projected mode dynamics, normal mode analysis was used to store each vibrational mode and its respective eigenvectors, Li j (i = 1,2,3,....3N ), which represent a set of eigenvectors for the corresponding jth normal mode (1 < j < 3N-6, i.e., apart from rigid rotations and translations). In general, the coupling of these normal modes is present during a molecular dynamics trajectory. Taking a suitable linear combination of these modes, we can generate a set of new modes. We then calculated the projections of the two MD trajectories in both vacuum and solvent of our model proteins onto the normal modes of the respective proteins. First, we determined the linear transformations of these modes into each velocity trajectory for which a new set of trajectories was generated based on the specific normal mode. These transformations were applied to each time step to obtain the trajectories Rsvel ( n*?t) (solvated proteins) and Rvvel (n*?t) (protein in vacuum) aligned to the normal modes, where n enumerates the time steps and Rvel is a 3N-dimensional vector encompassing the velocity of the N atoms in the protein. Moreover, the newly created velocity trajectories for the selective mode Lij are used to interpret the vibrational density of states projected onto the mode. Our comparison of the internal dynamics of solvated and non-solvated proteins has shown that the dynamic influence of the solvent is significant for the skeletal motions of the proteins. Using this method, we can calculate the boson frequency and its influence on the solvent at different cryogenic temperatures. |
Monday, March 20, 2023 6:12AM - 6:24AM |
AA09.00007: Modeling current blockade in a dual nanopore device Aniket Bhattacharya, Swarnadeep Seth We study current blockade (CB) of molecular features (markers) on a dsDNA construct translocating through a multiscan dual nanopore (NP) setup [1] using a volumetric occupation model of the CB for species inside or in the vicinity of the NP. The simulated reconstruct of the current traces in silico using Brownian dynamics (BD) obtained for different types of markers of various architecture contain relevant information that we later deconvolute by improving the signal-to-noise ratio and accounting for the velocity corrections [2]. These in-silico studies are important to understand the effect of tension propagation [2,3] on the current traces when multiple tags of different origins are present on a Kbp long dsDNA. The volumetric CB algorithm is quite general, and we choose the model parameters by comparing the exact CB data from simulation of an electrokinetic BD model (EKBD) where the co-ions and counter-ions flow through the NP provides the CB directly. We further validate our simulation results by comparing the experimental CB data for a 16.5 μm long λ-phage DNA with 15 oligo-tags [4] to further fine tune our BD model. |
Monday, March 20, 2023 6:24AM - 7:00AM |
AA09.00008: Principles of cellular control of condensates Invited Speaker: David Zwicker Biomolecular condensates are crucial for the spatiotemporal organization of the interior of cells. Condensates typically form since some biomolecules phase separate from the remaining cellular fluid. However, it is unclear why particular condensates form at particular locations and times. To unveil part of this mystery, I will present two principles that cells use to control condensates. First, I will focus on multicomponent phase separation. Ι will show that tuning the interactions between biomolecules allows controlling which condensates form, independent of the cellular composition. Evolution could thus have optimized proteins to form condensates robustly. Second, I will focus on driven chemical reactions that affect the condensate material. For instance, cells use post-translational modifications to modify the interactions of biomolecules. I will show that such reactions can control where and when condensates grow and how large they get. These two examples demonstrate that living cells can regulate size, number, and location of their condensates. |
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