Bulletin of the American Physical Society
APS March Meeting 2021
Volume 66, Number 1
Monday–Friday, March 15–19, 2021; Virtual; Time Zone: Central Daylight Time, USA
Session P12: Physics of Proteins IIIFocus Live
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Sponsoring Units: DBIO Chair: Dongping Zhong, Ohio State University - Columbus; Wei Wang, Nanjing Univ |
Wednesday, March 17, 2021 3:00PM - 3:36PM Live |
P12.00001: Building blocks of protein structure – physics meets biology Invited Speaker: Tatjana Skrbic The native state structures of globular proteins are stable and well-packed indicating that self-interactions are favored over protein-solvent interactions under folding conditions. We use this as a guiding principle to derive the geometry of the building blocks of protein structures – alpha helices and strands assembled into beta-sheets – with no adjustable parameters, no amino acid sequence information, and no chemistry. There is an almost perfect fit between the dictates of mathematics and physics and the rules of quantum chemistry. Our theory establishes an energy landscape that channels protein evolution by providing sequence-independent platforms for elaborating sequence-dependent functional diversity. Our work highlights the vital role of discreteness in life with implications for the creation of artificial life and on the nature of life elsewhere in the cosmos. |
Wednesday, March 17, 2021 3:36PM - 3:48PM Live |
P12.00002: In-silico epitope prediction against the Lassa virus glycoprotein Prabin Baral, Elumalai Pavadai, Bernard S Gerstman, Prem Prasad Chapagain The Lassa virus (LASV) is an ambisense RNA virus that causes severe hemorrhagic fever with a high fatality rate in humans in West and Central Africa. No FDA approved drugs or vaccines are available for the treatment of LASV as of now. Molecular details can be helpful in creating drugs that disrupt the life-cycle of the virus. A potential target for vaccines is the LASV glycoprotein complex (GP) situated on the virion envelope that plays key roles in LASV growth, cell tropism, host range, and pathogenicity. Using various molecular computational tools, we have identified LASV GP major histocompatibility complex (MHC) class I and II T cell epitopes. Prediction tools based upon both structure and sequence allowed us to identify LASV GP B cell epitopes which were further filtered based on a consensus approach. The strongly binding alleles to the MHC-I T-cell epitopes were used for molecular docking simulations and the complexes were relaxed with molecular dynamics simulations to investigate on the atomic level the interaction and dynamics of the epitope-allele complexes. Such studies may provide guidance in the design and development of LASV vaccines and further experimental validation of these epitopes will help in facilitating stimulation of T and B cell antibodies against LASV. |
Wednesday, March 17, 2021 3:48PM - 4:00PM Live |
P12.00003: Computational biomimetic-inspired modifications on the reaction and geometry of the FeNi Hydrogenase active site Meghan McGreal, Jason Goodpaster We performed a KS-DFT study of the catalytic cycle of FeNi Hydrogenase. We found that the catalytic cycle is dependent on the rigidity of the active site structure which is modulated by the surrounding enzyme, as well as electronic effects on the Fe and Ni atoms. Work has been done to attempt to replicate the activity of this enzyme in the lab to create biomimetic analogues, however the TOFs and overpotentials of these analogues differ significantly from the native enzyme. We performed calculations using biomimetic inspired changes to the computational model to observe effects on catalysis. Common biomimetic changes include replacing the CN ligands on the Fe with cp/cp* ligands, however significant structural changes were found, increasing the energetics and inhibiting the creation of the µ-H bound between Fe and Ni. To further study the ligand environment on Fe, we compared how the electron withdrawing or donating nature of the bound ligands influence the reaction. Results indicate that the electron withdrawing nature of the CN ligands is integral for efficient catalysis. Currently, other active site changes such as the inclusion of pdt ligands are being tested to create a comprehensive picture of how these changes influence the reaction profile and structure of the active site. |
Wednesday, March 17, 2021 4:00PM - 4:12PM Live |
P12.00004: A protein that remembers its past: Glassy behavior in an intrinsically disordered protein Ian Morgan, Gil Rahamim, Roy Beck, Omar A. Saleh Previously, we have shown that an intrinsically disordered protein construct displays two signatures of glassy behavior, logarithmic relaxation and a Kovacs memory effect, in response to changes in applied tension. With a combination of experiments and molecular dynamics simulations, we show that this glassy behavior can be attributed to multiple, independent, and local hydrophobic patches in the disordered protein that give rise to a broad distribution of relaxation timescales. This result is unexpected given the strongly polyampholytic nature of the protein. We present a mechanism by which conformational heterogeneity creates a rich mechanical response in single polymers. This mechanism is likely to apply to other disordered proteins. |
Wednesday, March 17, 2021 4:12PM - 4:24PM Live |
P12.00005: Glycine Shows Preference for Polyproline II Indicating Greater Role for Amino Acid Backbone Brian Andrews, Shuting Zhang, Reinhard Schweitzer-Stenner, Brigita Urbanc Amino acid residues exhibit conformational preferences in water and it is still unclear whether the preferences are attributed to properties of the amino acid backbone or side chain. A glycine-based peptide, which lacks a heavy-atom side chain, is a good model for examining the potential role of the backbone in amino acid conformational preferences. In this work, triglycine (GGG), which is intrinsically disordered due to its short length, is simulated using three commonly used Molecular Dynamic (MD) force fields. The central glycine of GGG is analyzed and compared to previously published spectroscopic data which demonstrates pPII is the dominant state in the conformational ensemble. The pPII propensity of the central glycine is comparable to that of the central alanine in GAG which implies the backbone is responsible for high pPII content. Further analysis shows that backbone-water hydrogen bonding is the mechanism that promotes this preference and pPII is less prevalent when GGG is immersed in solvents with limited hydrogen bonding capabilities. [B. Andrews, S. Zhang, R. Schweitzer-Stenner, and B. Urbanc, Glycine in Water Favors the Polyproline II State, Biomolecules 10, 1121 (2020)] |
Wednesday, March 17, 2021 4:24PM - 4:36PM Live |
P12.00006: Visualizing Amino Acid Substitutions in Physicochemical Space for Machine Learning Louis Nemzer Single amino acid substitutions are associated with certain inherited genetic disorders, such as sickle cell disease and hemochromatosis. To help sift through the large genomic databases now available, a new method of visualizing the physical and chemical changes as 3D vectors is proposed. In a principal component analysis space, the most important axes can be interpreted as "size," "hydrophobicity," and "charge." It can be shown that substitutions accessible by single nucleotide changes are strongly correlated with directions in this space, based on the codon position and mutation type. This illustrates the granular control available under the canonical genetic code for potentially beneficial mutations conferring a heterozygote advantage. This work can be applied to machine learning algorithms to better understand the underlying mechanisms behind these hereditary conditions. Other potential applications include the development of new therapeutics via rational protein design, as well as an improved theoretical basis for understanding directed and natural protein evolution. |
Wednesday, March 17, 2021 4:36PM - 4:48PM Live |
P12.00007: Did proteins evolve structural asymmetry for faster co-translational folding? John McBride, Tsvi Tlusty
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Wednesday, March 17, 2021 4:48PM - 5:00PM Live |
P12.00008: Endogenous metabolite modulates protein-protein interactions in Escherichia coli Rachit Gupta, Ravi Chawla, Nicolas Perdomo, Kathy Rhee, Pushkar Lele Indole, an interspecies and inter-kingdom signaling molecule, is produced by various species of bacteria. Indole regulates several aspects of bacterial physiology, including cell division, motility, and chemotaxis. We hypothesize that these diverse regulatory roles likely arise due to indole’s ability to regulate intracellular protein-protein interactions and molecular motor functions. In this work, we studied the influence of indole on the functioning of a large, multimeric protein complex-the flagellar motor-in E. coli. We monitored the response of individual motors in live cells upon treatment with indole. The response was consistent with a model where the conformations of component protein subunits flipped due to the metabolite, indicating that indole likely reduces the free energy differences between the tensed and relaxed states of individual proteins in the complex. Measurements also revealed decrease in membrane potential due to indole. We employed an Ising-based to quantify the effects of indole on motor functions. Our calculations suggest that indole decreases nearest neighbor interactions in multi-subunit complexes within the motor. We show that these regulatory properties of indole control E. coli’s motility and their ability to colonize surfaces. |
Wednesday, March 17, 2021 5:00PM - 5:12PM Live |
P12.00009: Function of a viral genome packaging motor from bacteriophage T4 is insensitive to DNA sequence Douglas Smith, Youbin Mo, Nick Keller, Damian Deltoro, Neeti Ananthaswamy, Stephen Harvey, Venigalla Rao Many viruses employ motors during assembly to translocate DNA into capsids. Previous reports raise questions if motor function depends on DNA sequence: i) The phage T4 motor exhibits large velocity fluctuations and pauses and slips, ii) Evidence suggests that the phage phi29 motor contacts DNA bases, and iii) a “B-A scrunchworm” model predicts that “A-philic” sequences that transition more easily to A-form would alter function. Here, we use optical tweezers measurements to compare translocation of phage, plasmid, and synthetic A-philic, GC rich sequences by the T4 motor. We observed no significant differences in motor velocities, even with A-philic sequences predicted to show higher rate, no significant changes in motor pausing, and only modest changes in slipping. To more generally test sequence dependence, we conducted correlation analyses across pairs of events. No significant correlations in packaging rate, pausing, or slipping versus position were detected across repeated measurements with different DNA sequences. These studies suggest that the viral motor insensitive to DNA sequence and fluctuations in packaging velocity, pausing, and slipping are primarily stochastic temporal events. |
Wednesday, March 17, 2021 5:12PM - 5:24PM Live |
P12.00010: Allosteric communications between protein domains via linker and substrate modulate the function SUSANTA SARKAR Degradation of collagen by matrix metalloprotease 1 (MMP1) is a model system to study allostery because the catalytic domain alone cannot degrade collagen. Both the catalytic and hemopexin domains are necessary, suggesting the essential role of allostery in function. We attached fluorescent dyes at two specific sites on the two domains of MMP1 to measure inter-domain dynamics. We calculated the distance between the two locations from the single molecule Forster Resonance Energy Transfer (smFRET) between the two dyes, measured using a Total Internal Reflection Fluorescence (TIRF) microscope. Low FRET conformations, where the two MMP1 domains are well-separated, are functionally relevant. These conformations are present in active MMP1 but significantly absent in inactive MMP1. Tetracycline, an MMP1 inhibitor, inhibits low FRET conformations. MMP9, an MMP1 enhancer, leads to more low FRET. Molecular dynamics (MD) simulations reproduce experimental features. More low FRET conformations are accompanied by more openings of the catalytic pocket, enabling the substrate to get closer to the catalytic site of MMP1. MD simulations further revealed that allosteric communications between the two MMP1 domains could be functionally influenced by collagen even when the linker is absent. |
Wednesday, March 17, 2021 5:24PM - 5:36PM Live |
P12.00011: Langevin Equations for Macromolecules in Body-Fixed Frames Jesse Hall Molecular Dynamics (MD) simulations using empirical all-atom potentials and explicit solvent molecules result in high-resolution molecular trajectories, but analytical methods are required to decompose the complex results into the essential physiologically relevant motions and their associated timescales. These methods are generally used to analyze trajectories viewed from a body-fixed frame, yet current methods do not make explicit the particular choice of frame, and any coupling between global translation and rotation and internal shape fluctuations is ignored. We present a Langevin equation for systems of interacting particles, based on a previous approach to Langevin mode analysis, in the canonical coordinates of an arbitrary body-fixed frame that accounts for these frame effects and couplings. In addition, the equations of motion allow linearization of the internal dynamics while preserving the three-dimensional structure of the molecule and can be directly simulated once the parameters have been fit to an MD trajectory, serving as a reduced order model of the molecule in an implicit solvent. |
Wednesday, March 17, 2021 5:36PM - 5:48PM Live |
P12.00012: A mass spectrometer for single-molecule protein sequencing Nicholas Drachman, Derek Stein There is a rapidly expanding research effort to sequence proteins at the single-molecule level. Conventional protein sequencing relies on electrospray ionization mass spectrometry, but it is generally thought that alternative approaches are needed for single-molecule sequencing. This is not due to any problems inherent to mass spectrometry, which has single ion sensitivity and superb resolution. Rather, it is due to the chaotic and inefficient nature of electrospray ionization, resulting in only a small fraction of the sample molecules arriving at the mass analyzer. Here we report the development of a new mass spectrometry technique featuring a nanocapillary ion source capable of emitting single amino acid ions directly into high vacuum from aqueous solution, sidestepping the drawbacks of conventional electrospray. Emitted amino acids are focused by a set of ion optics and separated by a magnetic sector before striking an array of single ion detectors. We show that this instrument can detect and distinguish different amino acids with orders of magnitude greater efficiency than conventional electrospray. Adoption of these nanocapillary ion sources could open the door to single-molecule protein sequencing and single cell proteomics. |
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