Bulletin of the American Physical Society
APS March Meeting 2017
Volume 62, Number 4
Monday–Friday, March 13–17, 2017; New Orleans, Louisiana
Session P6: Virus Capsid Protein DynamicsFocus
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Sponsoring Units: DBIO Chair: Wei Wang, Nanjing University, Nanjing, China Room: 265 |
Wednesday, March 15, 2017 2:30PM - 2:42PM |
P6.00001: Computational design of hepatitis C vaccines using empirical fitness landscapes and population dynamics Gregory Hart, Andrew Ferguson Hepatitis C virus (HCV) afflicts 170 million people and kills 350,000 annually. Vaccination offers the most realistic and cost effective hope of controlling this epidemic. Despite 25 years of research, no vaccine is available. A major obstacle is the virus' extreme genetic variability and rapid mutational escape from immune pressure. Improvements in the vaccine design process are urgently needed. Coupling data mining and maximum entropy inference, we have developed a computational approach to translate sequence databases into empirical fitness landscapes. These landscapes explicitly connect viral genotype to phenotypic fitness and reveal vulnerable targets that can be exploited to rationally design vaccines. These landscapes represent the mutational "playing field" over which the virus evolves. We have integrated them with agent-based models of the viral mutational and host immune response, establishing a data-driven multi-scale immune simulator. We have used this simulator to perform in silico screening of HCV immunogens to rationally design vaccines to both cripple viral fitness and block escape. By systematically identifying a small number of promising vaccine candidates, these models can accelerate the search for a vaccine by massively reducing the experimental search space. [Preview Abstract] |
Wednesday, March 15, 2017 2:42PM - 2:54PM |
P6.00002: Atomistic Simulations of the pH Induced Functional Rearrangement of Influenza Hemagglutinin Xingcheng Lin, Jeffrey Noel, Qinghua Wang, Jianpeng Ma, Jose Onuchic Influenza hemagglutinin (HA), a surface glycoprotein responsible for the entry and replication of flu viruses in their host cells, functions by starting a dramatic conformational rearrangement, which leads to a fusion of the viral and endosomal membranes. It has been claimed that a loop-to-coiled-coil transition of the B-loop domain of HA drives the HA-induced membrane fusion. On the lack of dynamical details, however, the microscopic picture for this proposed ``spring-loaded'' movement is missing. To elaborate on the transition of the B-loop, we performed a set of unbiased all-atom molecular dynamics simulations of the full B-loop structure with the CHARMM36 force field. The complete free-energy profile constructed from our simulations reveals a slow transition rate for the B-loop that is incompatible with a downhill process. Additionally, our simulations indicate two potential sources of kinetic traps in the structural switch of the B-loop: Desolvation barriers and non-native secondary structure formation. The slow timescale of the B-loop transition also confirms our previous discovery from simulations using a coarse-grained structure-based model, which identified two competitive pathways both with a slow B-loop transition for HA to guide the membrane fusion. [Preview Abstract] |
Wednesday, March 15, 2017 2:54PM - 3:06PM |
P6.00003: Simulations of polymorphic icosahedral shells assembling around many cargo molecules Farzaneh Mohajerani, Jason Perlmutter, Michael Hagan Bacterial microcompartments (BMCs) are large icosahedral shells that sequester the enzymes and reactants responsible for particular metabolic pathways in bacteria. Although different BMCs vary in size and encapsulate different cargoes, they are constructed from similar pentameric and hexameric shell proteins. Despite recent groundbreaking experiments which visualized the formation of individual BMCs, the detailed assembly pathways and the factors which control shell size remain unclear. In this talk, we describe theoretical and computational models that describe the dynamical encapsulation of hundreds of cargo molecules by self-assembling icosahedral shells. We present phase diagrams and analysis of dynamical simulation trajectories showing how the thermodynamics, assembly pathways, and emergent structures depend on the interactions among shell proteins and cargo molecules. Our model suggests a mechanism for controlling insertion of the 12 pentamers required for a closed shell topology, and the relationship between assembly pathway and BMC size polydispersity. In addition to elucidating how native BMCs assemble,our results establish principles for reengineering BMCs or viral capsids as customizable nanoreactors that can assemble around a programmable set of enzymes and reactants. [Preview Abstract] |
Wednesday, March 15, 2017 3:06PM - 3:42PM |
P6.00004: Measuring phenotypic variability and plasticity in influenza A virus using multispectral viral strains Invited Speaker: Michael Vahey Despite relevance to human health, the mechanisms of enveloped virus assembly remain largely mysterious. This is particularly true of influenza A virus (IAV), which (unlike viral capsids with stereotyped shape and composition) forms heterogeneous particles whose assembly cannot be described in terms of equilibrium thermodynamics. Although the ability to assemble into particles with diverse size and composition could have important implications for infectivity, understanding how virion-to-virion differences arise and how they ultimately influence virus replication has proven challenging due to the lack of available tools for studying the assembly process. To address this challenge and establish a dynamic picture of how IAV assembles, we have developed virus strains that harbor small, non-disruptive fluorescent tags on each of the virus's five major structural proteins. Using these multispectral strains, we are able to quantify the protein composition and dynamics of virions as they assemble in live infected cells - measurements that have been previously inaccessible, and which reveal subpopulations of virus that favor either the binding or destruction of host receptors. The occupancy of these different subpopulations is malleable, shifting in response to environmental stimuli, including antiviral drugs that block receptor-destruction. In complex environments like the human respiratory tract, this phenotypic diversity could act as an evolutionary hedge. [Preview Abstract] |
Wednesday, March 15, 2017 3:42PM - 3:54PM |
P6.00005: High-resolution structure, interactions, and dynamics of self-assembled virus-like partilces Uri Raviv Using SAXS, in combination with Monte Carlo simulations, and our unique solution x-ray scattering data analysis program, we resolved at high spatial resolution, the manner by which wtSV40 packages its 5.2kb circular DNA about 20 histone octamers in the virus capsid (Figure 1). This structure, known as a mini-chromosome, is highly dynamic and could not be resolved by microscopy methods (Nucleic Acid Research, 41, 1569, 2013). Using time-resolved solution SAXS, stopped-flow, and flow-through setups the assembly process of VP1, the major caspid protein of the SV40 virus, with RNA or DNA to form virus-like particles (VLPs) was studied in msec temporal resolution. By mixing the nucleotides and the capsid protein, virus-like particles formed within 35 msec, in the case of RNA that formed T$=$1 particles, and within 15 seconds in the case of DNA that formed T$=$7 particles, similar to wt SV40. The structural changes leading to the particle formation were followed in detail (J. Am. Chem. Soc. 134, 8823, 2012). More recently, we have extended this work to study the assembly of HBV virus-like particles. [Preview Abstract] |
Wednesday, March 15, 2017 3:54PM - 4:06PM |
P6.00006: Mechanisms of virus assembly on membranes Guillermo Lazaro, Michael Hagan We present a computational model motivated by icosahedral enveloped viruses, which consist of nucleocapsid (a protein shell encasing the genome) and an outer envelope composed of a lipid membrane and transmembrane glycoproteins. Viruses acquire their envelope by budding through a host cell membrane. Despite extensive experimental efforts, it remains an open question whether the nucleocapsid is necessary for budding (nucleocapsid-driven assembly), or whether interactions between glycoproteins are sufficient to simultaneously drive membrane deformation and assembly of an icosahedral structure (glycoprotein-driven assembly). To study this question, we use a coarse-grained computational model for the nucleocapsid, glycoproteins, and the membrane. Our simulations demonstrate that glycoproteins alone are sufficient to drive budding; however, barriers due to membrane elasticity can lead to malformed capsids lacking icosahedral symmetry. In contrast, with a nucleocapsid present, icosahedral structures form over a broad range of parameter values. Our simulations also identify a key role for glycoprotein geometry in reshaping the membrane and avoiding membrane deformations that frustrate assembly. [Preview Abstract] |
Wednesday, March 15, 2017 4:06PM - 4:42PM |
P6.00007: Atomic Force Microscopy of virus capsids uncover the interplay between mechanics, structure and function Invited Speaker: Pedro J de Pablo The basic architecture of a virus consists of the capsid, a shell made up of repeating protein subunits, which packs, shuttles and delivers their genome at the right place and moment. Viral particles are endorsed with specific physicochemical properties which confer to their structures certain meta-stability whose modulation permits fulfilling each task of the viral cycle. These natural designed capabilities have impelled using viral capsids as protein containers of artificial cargoes (drugs, polymers, enzymes, minerals) with applications in biomedical and materials sciences. Both natural and artificial protein cages (1) have to protect their cargo against a variety of physicochemical aggressive environments, including molecular impacts of highly crowded media, thermal and chemical stresses, and osmotic shocks. Viral cages stability under these ambiences depend not only on the ultimate structure of the external capsid, which rely on the interactions between protein subunits, but also on the nature of the cargo. During the last decade our lab has focused on the study of protein cages with Atomic Force Microscopy (AFM) (figure 1). We are interested in stablishing links of their mechanical properties with their structure and function. In particular, mechanics provide information about the cargo storage strategies of both natural and virus-derived protein cages (2,3). Mechanical fatigue has revealed as a nanosurgery tool to unveil the strength of the capisd subunit bonds (4). We also interrogated the electrostatics of individual protein shells (5). Our AFM-fluorescence combination provided information about DNA diffusing out cracked-open protein cages in real time (6). [1] Llauro et al. Nanoscale, 2016, 8, 9328. [2] Hernando-Perez et al. Small, 2012, 8, 2336. [3] Ortega-Esteban et al. ACS Nano, 2015, 9, 10826. [4] Hernando-Perez et al. Nature Communications, 2014, 5, 4520. [5] Hernando-Perez et al. Nanoscale, 2015, 7, 17289. [6] Ortega-Esteban et al. ACS Nano, 2015, 9, 10571. [Preview Abstract] |
Wednesday, March 15, 2017 4:42PM - 4:54PM |
P6.00008: The role of genome on self-assembly of viral shell Siyu Li, Roya Zandi Simple viruses self-assemble spontaneously and encapsulate their genome into a shell called the capsid. This process is mainly driven by the attractive interaction between capsid and genome. We perform a number of Brownian Dynamics simulations using coarse-grained models to monitor the growth of the virus. The energetics of the capsid is governed by the stretching and bending energies. The polymer is built from the Lennard Jones particles that interact with the shell through electrostatic interactions. The results show that genome structure has an impact on the capsid symmetry while genome radius of gyration plays a key role on the final capsid size as well as the triangulation number. [Preview Abstract] |
Wednesday, March 15, 2017 4:54PM - 5:06PM |
P6.00009: Replica-Exchange Wang-Landau Simulations of a Semi-flexible H0P Lattice Protein Model for Crambin Alfred Farris, Guangjie Shi, Thomas W\"ust, David P. Landau The oft studied hydrophobic-polar (HP) lattice protein model has the disadvantage of producing highly degenerate ground states, which is in disagreement with the unique native states found in real proteins. The recently proposed H0P model adds a "neutral" monomer (0), in an attempt to more precisely account for the hydrophobicity of different amino acid residues and has been shown to drastically decrease the ground state degeneracy without significantly increasing sampling difficulty\footnote{G. Shi, T. W\"ust, Y. W. Li, and D. P. Landau, J. Phys.: Conf. Ser. 640, 012017 (2015)}. Here we proposed a further modification to the model by introducing an energetic penalty for "bends" in the protein, effectively accounting for the natural rigidity of real proteins\footnote{G. Shi, A. C.K. Farris, T. W\"ust, and D. P. Landau, J. Phys.: Conf. Ser. 686, 012001 (2016)}. Using replica-exchange Wang-Landau sampling, we investigated such a semi-flexible H0P model for Crambin, a hydrophobic plant protein consisting of 46 amino acids. With these modifications to the original HP model, we uncovered a new step in the folding process, and obtained a single, non-degenerate (unique) ground state. [Preview Abstract] |
(Author Not Attending)
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P6.00010: Architecture of Allosteric Materials and Edge Modes Le Yan, Riccardo Ravasio, Carolina Brito, Matthieu Wyart Allostery, a long-range elasticity-mediated interaction, remains the biggest mystery decades after its discovery in proteins. We introduce a numerical scheme to evolve functional materials that can accomplish a specified mechanical task. In this scheme, the number of solutions, their spatial architectures and the correlations among them can be computed. As an example, we consider an ``allosteric'' task, which requires the material to respond specifically to a stimulus at a distant active site. We find that functioning materials evolve a less-constrained trumpet-shaped region connecting the stimulus and active sites and that the amplitude of the elastic response varies non-monotonically along the trumpet. As previously shown for some proteins, we find that correlations appearing during evolution alone are sufficient to identify key aspects of this design. Finally, we show that the success of this architecture stems from the emergence of soft edge modes recently found to appear near the surface of marginally connected materials. Overall, our in silico evolution experiment offers a new window to study the relationship between structure, function, and correlations emerging during evolution. [Preview Abstract] |
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