Bulletin of the American Physical Society
APS March Meeting 2019
Volume 64, Number 2
Monday–Friday, March 4–8, 2019; Boston, Massachusetts
Session V54: Sequence and Charge Driven Bio- and Bio-inspired Macromolecular AssemblyFocus
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Sponsoring Units: DPOLY DBIO Chair: Charles Sing Room: BCEC 254A |
Thursday, March 7, 2019 2:30PM - 3:06PM |
V54.00001: Theoretical Perspectives on Cellular Compartmentalization by Phase Separation Invited Speaker: Hue Sun Chan Compartmentalization is essential for many cellular functions. Besides organelles encapsulated by lipid membranes—mitochondria and the nucleus, e.g., dynamic non-membrane-bound compartments also exist in the eukaryotic cell. These include stress granules, germ granules, the nucleolus, and many others. Recent investigations indicate that these bodies behave like mesoscopic liquid droplets. Referred to as “membraneless organelles”, or “biomolecular condensates”, they are underpinned to a significant extent by liquid-liquid phase separation (LLPS) of intrinsically disordered proteins (IDPs) and nucleic acids. Their formation/dissolution is governed largely by the information encoded in the sequences of nucleic acids and proteins. To gain physical insights into this novel phenomenon, we developed analytical theories1-3 and simulation models4,5 for sequence-specific IDP LLPS. Our effort rationalizes experiments on the DEAD-box RNA helicase Ddx4, elucidates the effect of sequence charge patterns on LLPS6, and points to a “fuzzy” mode of molecular recognition by charge pattern matching that likely bears on whether different IDP species remain miscible or demix upon LLPS to serve their biological functions7. IDP LLPSs depends on temperature and hydrostatic pressure8. As a first step toward understanding these behaviors, we show that the trend of such dependence can be qualitatively rationalized by empirical3 and atomic9,10 modeling of elementary hydrophobic interactions. |
Thursday, March 7, 2019 3:06PM - 3:18PM |
V54.00002: Transfer Matrix Theory Model of Sequence-Dependent Polyampholyte Phase Separation Jason Madinya, Charles E. Sing Intrinsically disordered proteins (IDPs) participate in many critical biological functions within the cell. These proteins lack a well-defined structure and can take on many conformations depending on its sequence and local environment. IDPs can be modeled as polyampholytes and can undergo a liquid-liquid phase separation that is primarily driven by electrostatic interactions. The charge sequence along the polymer is critical to the solution behavior. In this work, we present a Transfer Matrix (TM) model to describe this liquid-liquid phase separation as a function of charge sequence. We show how the TM theory is created for a polyampholyte, and how it can be used to determine the free energy of interaction between the polyampholyte and its local environment. In conjunction with the TM theory, we perform MD simulations of charge-patterned polyampholytes in solution to compare with the model. We find that increasing charge blockiness increases the tendency to undergo phase separation, limiting to the behavior typically seen in polymeric complex coacervates, while alternating positive and negative charges do not exhibit charge-induced phase separation. |
Thursday, March 7, 2019 3:18PM - 3:30PM |
V54.00003: Impact of complex coacervation on tau amyloid aggregation Yanxian Lin, Kate Zeng, Yann Fichou, Yuge Hu, Songi Han Amyloid aggregation of tau protein is implicated in human neurodegenerative diseases. While complex coacervation (CC) of tau and polyanion has shown both biological and pathological significance, its impacts on tau amyloid aggregation is not well understood. We report here recent findings and characterizations of tau-polyanion CC and its relationship with tau aggregation. We first demonstrate that tau can form complex coacervates with almost any polyanion. We found whether tau CC remains fluidic or solidifies towards fibrils is determined by the aggregation propensity of the CC forming constituents, not the CC forming process. Further, we closely examined changes of aggregation kinetics of tau resulting from the CC environment, and found the collision dependence of tau aggregation to be reduced by CC. Finally, we investigated the effect of CC on the fibrillization kinetics and seeding activity by tau fibrils. |
Thursday, March 7, 2019 3:30PM - 3:42PM |
V54.00004: Effect of pH on polymer adsorption and bridging in a two oppositely charged nanoparticle/protein system Rituparna Samanta, Venkatraghavan Ganesan We discuss the results of molecular simulations of charged particles in presence of oppositely charged, dissociable polymers. The effect of pH on adsorption and bridging characteristics of the polyelectrolyte for both homogeneous and heterogeneously charged particles is studied. We have studied the effect of charge distribution on the particles, charge and size of polyelectrolytes and concentration of polymers on adsorption, bridging and effective interactions between the particles. |
Thursday, March 7, 2019 3:42PM - 3:54PM |
V54.00005: Tuning interactions between hybrid physical-covalent rigid rods made of computationally designed coiled coils by peptide sequence manipulation Nairiti Sinha, Rajkumar Misra, Rui Guo, Christopher Kloxin, Jeffery G Saven, Darrin Pochan Application of computational design to biomolecular sequence, structure and function prediction provides vast opportunity in artificial biomaterial construction and assembly. Non-natural coiled coils, oligomers of α-helical peptides, can be designed to assemble in solution by computational sequence discovery and manipulation via strategic placement of amino-acids exposed to the solvent. Utilizing a hybrid assembly pathway, computationally designed homotetramer coiled coil bundles are linked in an end-to-end fashion resulting in rigid rods of bundles or “bundlemers”. Transmission Electron Microscopy (TEM) and Small-Angle Neutron Scattering (SANS) confirm that the rods have a 2 nm cross-section commensurate with that of a single bundle. SANS is also used to study inter-rod interactions for peptides that carry increasing net negative charge. Differences in local repulsive interactions between rods is observed due to changes in rod charge density, which is responsive to pH and ionic strength of the solution. Larger percolated clusters of rods which form due to local patchiness of interaction sites is also confirmed. This control of solution structure with fine control of the charged state, length, dispersity and concentration of bundlemer rods will be discussed. |
Thursday, March 7, 2019 3:54PM - 4:06PM |
V54.00006: Influence of Charge Sequence on the Adsorption of Polyelectrolyte Solution on to Polyelectrolyte Brush Vaidyanathan Sethuraman, Michael P McGovern, David Clark Morse, Kevin Dorfman We use coarse-grained MD to elucidate the role of charge sequence on the adsorption efficacy of oppositely charged free polyelectrolytes on to a polyelectrolyte brush. We consider four different model systems wherein the free and the brush polyelectrolytes can have either brush or alternating charge sequence. Our model treats the polyelectrolytes in a bath of implicit solvent, excess salt and explicit counterions. Adsorption efficiency is highest when both free and brush polyelectrolytes possess a block charge sequence, and it is lowest when both free and brush polyelectrolytes possess an alternating charge sequence. By computing the free energy, internal energy and entropy of adsorption using umbrella sampling methods, we find that the origin of the differences in adsorption efficiency for different charge sequences is enthalpic. Additionally, equilibrium conformations for different charge sequences reinforce the results obtained from energetic calculations. When the number of brush polymers is more than that of the free polymers, a spatial heterogeneity is observed in the charge distribution within the brush region which is strongly dependent on the charge sequence of free and brush polyelectrolytes. |
Thursday, March 7, 2019 4:06PM - 4:18PM |
V54.00007: Biomolecules for non-biological things: 1-D and 2-D polymer formation through peptide design and solution assembly Darrin Pochan A new solution assembled system comprised of theoretically designed coiled coil bundle motifs will be introduced. The molecules and nanostructures are not natural sequences and provide opportunity for arbitrary nanostructure creation with peptides. With control of the display of all amino acid side chains (both natural and non-natural) throughout the peptide bundles, desired physical and covalent (through appropriate “click” chemistry) interactions have been designed to produce one and two-dimensional nanostructures. One-dimensional nanostructures span exotically rigid rod molecules that produce a wide variety of liquid crystal phases to semi-flexible chains, the flexibility of which are controlled by the interbundle linking chemistry. The two dimensional nanostructure is formed by physical interactions and are nanostructures not observed in nature. All of the assemblies are responsive to temperature since the individual bundle building blocks are physically stabilized coiled coil bundles that can be melted and reformed with temperature. Additional, novel nanostructures to be discussed include uniform nanotubes as well as the templated growth of metallic nanoparticle on and in peptide nanostructures. |
Thursday, March 7, 2019 4:18PM - 4:54PM |
V54.00008: Engineering protein and polyelectrolyte complexation for cellular applications Invited Speaker: Allie Obermeyer Oppositely charged polyelectrolytes are known to undergo a liquid-liquid phase separation, termed complex coacervation, under the appropriate solution conditions. Protein polyelectrolytes have also been shown to phase separate with polyelectrolytes. However, protein polymers differ significantly from synthetic polyelectrolytes. Proteins are polyampholytes, have low charge density, and frequently adopt a globular folded structure. These differences impact the complexation and phase separation of proteins with polyelectrolytes. These differences also make protein polymers interesting to study in this context; the charge, charge density, and charge orientation on proteins can be precisely controlled through genetic engineering. Additionally, it has recently been demonstrated that the phase separation of proteins is a fundamental mechanism for eukaryotic cellular compartmentalization. These phase separated membraneless organelles create distinct environments that are essential to cellular processes ranging from cell signaling to gene expression. Many membraneless organelles appear to have the same physical properties as complex coacervates – liquid-liquid phase separated mixtures of oppositely charged polyions. We are motivated to understand protein complex coacervation in order to enable new biological applications of these materials. Toward this end, we have investigated the complex coacervation of engineered proteins with synthetic and biological polyions to determine predictive design rules for protein phase separation. We have also used these design rules to promote phase separation of engineered proteins in vivo. |
Thursday, March 7, 2019 4:54PM - 5:06PM |
V54.00009: Conditions for complex coacervation of the microtubule-associated tau protein predicted from field theoretic simulations James McCarty, Yanxian Lin, Kris T Delaney, Glenn Fredrickson, Songi Han, Joan-Emma Shea The microtubule associated tau protein is a highly charged intrinsically disordered protein (IDP) that has been linked to neurodegenerative diseases including Alzheimer’s disease. Recently, tau has been shown to undergo a liquid-liquid phase transition, leading to speculation about how this process may mediate pathological tau fibrillization. To understand the thermodynamic driving forces of this process, we apply a discrete Gaussian-chain polyelectrolyte model and compute thermodynamic observables using a numerical technique known as field theoretic simulation (FTS). Results from FTS for this coarse-grained tau model reveal how the combination of charge distribution, salt concentration, and temperature-dependent excluded volume determine the observed phase diagram. Our results suggest new avenues for simulation to inform experimental design. Finally, we will comment on extensions of the model and applications to other IDPs. |
Thursday, March 7, 2019 5:06PM - 5:18PM |
V54.00010: Sequence Effects on Block Copolymer Self-Assembly through Tuning Chain Conformation and Segregation Strength Utilizing Sequence-Defined Polypeptoids Anastasia Patterson, Scott Danielsen, Beihang Yu, Emily C Davidson, Glenn Fredrickson, Rachel Segalman Polymers with precise sequence control offer the possibility of tuning segregation strength with comonomer sequence instead of chemical identity. We have synthesized polystyrene-b-polypeptoid block copolymers with different sequences of comonomers in the polypeptoid block, where nonpolar phenyl side chains are incorporated to tune compatibility with polystyrene. Using small-angle X-ray scattering, we see that these materials self-assemble into lamellae with domain spacings and order–disorder transition (ODT) temperatures varying with sequence, despite identical composition. The variation in the ODT suggests that sequence control at the monomer level alters segregation strength, and by comparing domain spacings and SCFT simulations, we find that the main driving force is likely chain conformational effects that localize comonomers at the block–block interface. However, trends seen in the ODT are not captured by SCFT simulations or effective χ parameters (measured in the disordered phase by approximating the copolypeptoid as a uniform block). The disagreement between measured thermodynamic properties and coarse-grained approaches like SCFT and effective χ points to the importance of molecular-scale effects in sequence-defined materials. |
Thursday, March 7, 2019 5:18PM - 5:30PM |
V54.00011: Kinetics of conformational changes in polyelectrolyte systems Swati Sen, Soumik Mitra, Arindam Kundagrami Equilibrium phase behavior of polyelectrolytes is well-studied in literature. The kinetics of conformational changes in such systems, however, has received sporadic attention, which has increased recently given its relevance to biological problems like protein-folding or biomedical processes like drug-delivery. Our group has been working on studying the time-dependent, inhomogeneous profiles of physical variables, such as mass and charge densities and osmotic stress, related to the swelling kinetics of polyelectrolyte gels. We will present our recent results obtained from the nonlinear theory that uses the expression of osmotic stress as a function of mass and charge densities, and hence is capable of addressing arbitrarily large deformations that are beyond the scope of traditional theories with linear stress-strain relationship. Considering issues like charge-regularization and role of elasticity and electrostatics, the major results we have obtained include estimation of effective elastic modulus, time-dependency of the size, and the relaxation times of charged gels as functions of its charge content, temperature, density of cross-links, and chemical affinity of the polymer and the solvent. |
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