Bulletin of the American Physical Society
APS March Meeting 2022
Volume 67, Number 3
Monday–Friday, March 14–18, 2022; Chicago
Session M06: Physics of Proteins I: Structure & Dynamics IIFocus Recordings Available
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Sponsoring Units: DBIO Chair: Aihua Xie, Oklahoma State U Room: McCormick Place W-178B |
Wednesday, March 16, 2022 8:00AM - 8:12AM |
M06.00001: Using core packing to assess the quality of NMR structures Alex T Grigas, Lynne Regan, Corey S O'Hern There are two main methods for determining protein structure on the atomic scale: X-ray crystallography and NMR spectroscopy. X-ray crystallography can provide the positions of all atoms in a protein, and thus little modeling is required to determine the protein's structure. NMR spectroscopy produces numerous restraints on atomic separations and angles, which can then be combined with existing force fields to determine a protein's structure. In contrast to X-ray crystallography, there are no accepted metrics of structure quality for NMR. In addition, there is a long-standing debate about whether NMR structures for a given protein are different from those from X-ray crystallography, and whether the differences are real or artifacts of the measurements. To address this question, we have analyzed all NMR structures deposited in the Protein DataBank (PDB) that contain the restraints used to generate NMR model structures. In comparison to high-resolution X-ray crystal structures, the set of the top 25% NMR structures with the greatest number and agreement with their restraints, includes a significant number of structures that possess more densely packed cores. Some of these NMR structures with overpacked cores possess large atomic overlaps, leading to high packing densities. However, other over-packed NMR structures have similar atomic overlap energies compared to x-ray crystal structures. We also carried out unrestrained and restrained molecular dynamics simulations of several proteins to determine whether the degree of overpacking in the cores of NMR structures is related to the number of NMR restraints that are satisfied. |
Wednesday, March 16, 2022 8:12AM - 8:24AM |
M06.00002: Proteins – a celebration of consilience Tatjana Skrbic, Trinh X Hoang, Achille Giacometti, Amos Maritan, Jayanth R Banavar Proteins are the common constituents of all living cells. They are molecular machines that interact with each other as well as with other cell products and carry out a dizzying array of functions with distinction. These interactions follow from their native state structures and therefore understanding sequence-structure relationships is of fundamental importance. What is quite remarkable about proteins is that their understanding necessarily straddles several disciplines. The importance of geometry in defining protein native state structure, the constraints placed on protein behavior by mathematics and physics, the need for proteins to obey the laws of quantum chemistry, and the rich role of evolution and biology all come together in defining protein science. Here we present an interdisciplinary framework that aims to marry ideas from Plato and Darwin and demonstrates an astonishing consilience between disciplines in describing proteins. We discuss the consequences of this framework on protein behavior. |
Wednesday, March 16, 2022 8:24AM - 9:00AM |
M06.00003: Impact of Water-Protein Interactions on Protein Dynamics(Nguyen Q. Vinh, Department of Physics and Center for Soft Matter and Biological Physics, Virginia Tech, Blacksburg, VA 24061) Invited Speaker: Vinh Q Nguyen Proteins function only in aqueous environments and their dynamics is strongly influenced by physiological conditions. The dynamics of hydration water as well as hydrated proteins lead to rotating and oscillating dipoles that, in turn, give rise to a strong megahertz to terahertz absorption. Investigating the impact of hydration on protein dynamics and the spectral features of water molecules influenced by protein, however, is extremely challenging because of the strong absorption of water in the megahertz to terahertz frequency region. In response, we have employed a broad-band megahertz to terahertz spectroscopy with ultrahigh precision, assisted by molecular dynamics simulations, to investigate the dynamics of water molecules within hydration shells of proteins as well as the collective vibrational motions of hydrated proteins, which are vital to protein conformation and functionality. Our results reveal that the dynamics of water molecules in a protein solution is heterogeneous, exhibiting a hierarchy of several distinct relaxation times ranging from ∼8 ps to 1 ns, and the hydration structure of a protein extend beyond the first hydration layer. The low-frequency collective vibrational modes of hydrated proteins have been identified and found to be sensitive to environmental conditions including temperature and hydration level. The results reveal critical information on hydrated protein dynamics and protein-water interfaces, which impact the biochemical functions and reactivity of proteins. |
Wednesday, March 16, 2022 9:00AM - 9:12AM |
M06.00004: Atomistic and coarse-grained molecular dynamics study of peptide-lipid membrane dissociation Ryan Smith, Ioan Kosztin Measuring and characterizing the strength of the interaction between individual proteins and lipid membranes, by means of single molecule experiments, is important for understanding the role of this interaction in cell function. For example, high precision AFM based dynamic force spectroscopy can be used to measure the dissociation force distribution, P(F), of peptides attached to lipid membranes. However, the interpretation of P(F) in terms of the standard Brownian escape process across a free energy barrier is complicated by the existence of several stochastic pathways along which dissociation may proceed. Thus, the barrier height (activation energy), U0, and the activation length, x0 , should be regarded as stochastic quantities with yet to be determined probability distribution. Here we show that prior distributions of U0 and x0 can be obtained from the potentials of mean force (PMF) calculated from either all atom (AA) or coarse grained (CG) molecular dynamics (MD) simulations. To this end, the PMFs of three Wimley-White pentapeptides (Ac-WLXLL, with guest residues X=R,I and L) interacting with two different lipid bilayers (zwitterionic POPC and charged POPG) are calculated using the umbrella sampling method. First we show that the PMFs from CG MD simulations are comparable to those obtained from AA MD simulations. The former, being almost two orders of magnitude more efficient than the latter, permits the effective calculation of an ensemble of PMFs, and consequently the construction of the probability densities of U0 and x0 . Finally, the obtained results are used to interpret P(F) obtained from AFM experiments. |
Wednesday, March 16, 2022 9:12AM - 9:24AM |
M06.00005: Photo-Switching in Crystalline OCP Robert R Thompson, Andrea G Markelz, Timothy Lafave, Deepu K George, Jeffrey A Mckinney Orange Carotenoid Protein (OCP) is a photoprotective protein in cyanobacteria. In solution under high UV intensity, OCP switches from its resting state, or orange state, OCPO, peak absorbance at 495nm, to its photoprotective red state, OCPR peak absorbance 515 nm. The transition involves a large scale structural reorganization that enables fluorescence quenching. Time resolved X-ray crystallography and anisotropic terahertz microspectroscopy (ATM) can measure the sequence of the structural and dynamical changes occurring with the transition, however these techniques require protein crystals, and to date photo switching has not been demonstrated in OCP crystals. Here we report the conditions to achieve crystal phase photoswitching. Using a homebuilt micro spectrometer, we found that in solution, photoswitching with 65 mW at 450 nm within 10 s results in a peak change in absorbance at 550 nm. Photoswitching for the crystals was found with the same power as the solution, but only after 2 min. of illumination. The red state appears to be irreversible after at least 2 days, and the peak in the change in the absorbance for the crystal phase shifts to 565 nm. The results provide the first demonstration that the early steps in photoprotective state transition are accessible in crystals. |
Wednesday, March 16, 2022 9:24AM - 9:36AM |
M06.00006: Structural Dynamics of Prefusion Spike Protein of SARS-CoV-2 and its Variants: Insights from Molecular Dynamics Mortaza Derakhshani Molayousefi, Ugochi Isu, Mahmoud Moradi The rapidly evolving COVID-19 pandemic has claimed many lives and crippled economies around the world. SARS-COV-2, the virus behind the pandemic, uses spike proteins to infect human cells by binding to ACE2 receptors on various host cells. Multiple mutants have emerged, among which there have been thriving variants with increased transmissibility and capacity for immune evasions. Static structures of wild-type spike proteins are insufficient to understand the evolving process of activation and infection. Here we have used microsecond-level molecular dynamics (MD) simulations to study the active and inactive states of the spike proteins on the wild-type, Alpha, Beta, Gamma, Epsilon, and Delta variants, as well as an engineered spike protein associated with the Moderna vaccine. Our simulations reveal specific mutations, which are responsible for the differential dynamic behavior of variants. These particular mutations could potentially be associated with higher transmissibility and immune evasion potential of the viruses by altering the activation path and active structures. This study provides insight into the dynamic behavior of the spike protein of different SARS-CoV-2 variants, which is key to identifying targets for the development of novel vaccines and therapeutic agents. |
Wednesday, March 16, 2022 9:36AM - 9:48AM |
M06.00007: Temperature Sensitive Contact Analysis Directs Hyperactive Enzyme Design. Dan Burns Homologous mesostable and thermostable enzymes exhibit markedly different thermostabilty and activities as a result of their unique amino acid sequences. This is a necessary consequence of an organism’s metabolism and environmental pressures of which temperature is the most prominent. The mechanisms by which sequence specific interactions tune the activity of an enzyme to a particular temperature is of fundamental importance for understanding protein functional dynamics and has significant implications for the design and application of synthetic enzymes. To this end we recently designed hybrid thermophilic/mesophilic variants of the C domain of bacterial Enzyme I (EIC) with modulated activity by hybridizing the disordered catalytic loops of each wild type with the remainder of the other wild type’s C domain. In order to reveal the residue level interactions encoding enzymatic activities, we employed Hamiltonian Replica Exchange Molecular Dynamics (HREMD) to sample the conformational ensemble across temperature of the disordered catalytic loops of these 4 EIC homologs. Employing Principal Component Analysis (PCA), we extracted and ranked residues according to their contact frequencies’ temperature sensitivity. We hypothesize that these residues have the strongest effect in tuning the enzymes’ activities to their physiological temperatures. To test our hypothesis we assayed 3 mutant thermophile EIC enzymes with mutations based on these most temperature sensitive contacts. We found a minimal mutation set to the thermophilic homolog (inactive at low temperature) that increased its activity at low temperature substantially toward that of the hybrid homolog. These results suggest an efficient computational approach for designing hyperactive thermophilic enzymes and a novel analysis method for studying protein dynamics across temperature and identifying key dynamical features not otherwise apparent. |
Wednesday, March 16, 2022 9:48AM - 10:00AM |
M06.00008: Characterizing Hydration Dynamics and Collective motions of Hemoglobin in Aqueous Solutions using High Sensitivity Dielectric Spectroscopy Huong Hoang, Vinh Q Nguyen Hemoglobin, the dominant component of mammals' red blood cells, is the oxygen and carbon-dioxide transport protein. Hemoglobin physically performs its function by changing the macromolecule shape in response to the change of the surrounding environment. In reality, hemoglobin molecules are surrounded by water molecules, the solvent of life, which is simple in formula but exhibits very complex chemical and physical properties. The incorporating of the complicated quaternary structure of hemoglobin and the hydrogen-bonding in the aqueous environment make a critical challenge in identifying their collective dynamics. Employing highly sensitive dielectric megahertz-to-terahertz frequency-domain spectroscopy, we are able to examine the dynamic of hemoglobin and the hydration structure at the molecular level. Temperature and solvent concentrations have been applied to clarify the effects of living factors on protein functions. The results help us to identify the protein-water interactions and hemoglobin dynamics that determine biochemical functions and reactivity of hemoglobin. |
Wednesday, March 16, 2022 10:00AM - 10:12AM |
M06.00009: Assignment of Protein Collective Structural Vibrations Steering Conformational Change Xing Liu, Andrea G Markelz Collective vibrations from elastic network models (ENM) have been used to predict protein intermediate state structures. The underlying assumption is that these vibrational displacements provide a trajectory towards the intermediate state conformation. In reality structural vibrations have small displacement amplitudes, insufficient to reach the intermediate state. Further ENM vibrations do not capture the complexity and variability of an all atom system which samples multiple configurations. Despite this variability, measurements of the anisotropic terahertz absorption find spectral structure for macroscopic protein samples indicating specific displacement directions concentrated in specific energy bands emerge from this complexity. This suggests that while no single vibration is responsible for a conformational transition, the overall dynamics of the system is biased towards the intermediate state displacements. Here we present strategies to assign the spectrally observed bands with structural displacements based on normal mode ensemble analysis (NMEA). A projection analysis on a full ensemble of vibrations of lysozyme using a vibrational displacement basis set from ENM shows narrow frequency ranges are dominated by specific displacements. As a second strategy, we examine correlations in structural displacements for resonant bands in the calculated anisotropic absorbance for the photo protective protein, orange carotenoid protein. |
Wednesday, March 16, 2022 10:12AM - 10:24AM |
M06.00010: Quality assessment of computational models of protein-protein interfaces Grace Meng, Alex T Grigas, Lynne Regan, Corey S O'Hern Protein-protein interactions are essential in many biological processes ranging from cellular signalling to enzymatic activity. Incorrect interactions such as protein aggregation can result in neurological diseases and other disorders. In this work, we describe novel methods to determine whether computational models of protein-protein interfaces are experimentally accurate or not. We first constructed a dataset of high-quality crystal structures of heterodimers and generated computational models of each complex using state-of-the-art docking methods. We focus on several features of the cores of the interfaces to classify the computational models, e.g. the number, atomic overlap energy, hydrophobicity, and packing fraction of the core residues at the interfaces. Using these features, we find important differences between the interfaces of experimentally determined structures and those in poor-quality computational models, or decoys. Based on these results, we developed a machine-learning classifier that can predict the quality of computational models even for interfaces that have not been studied experimentally. |
Wednesday, March 16, 2022 10:24AM - 10:36AM |
M06.00011: Monte Carlo simulations reveal limitations of the single-reaction-coordinate picture Sudeep Adhikari, Kevin S Beach The folding dynamics of biopolymers can be studied using a constrained random walk |
Wednesday, March 16, 2022 10:36AM - 10:48AM |
M06.00012: Non-ergodic internal dynamics of a globular protein observed over fourteen orders in time Liang Hong, Jun Li Protein internal motions have been assumed ergodic, i.e., dynamics of a single molecule over time resembles that of an ensemble. Here, by performing 254 single-molecule fluorescence resonance energy transfer (smFRET) experiments and 100 molecular dynamics (MD) simulations of a multi-domain globular protein, cytoplasmic protein-tyrosine phosphatase, we demonstrate by examining large ensembles that the interdomain motion varies widely between individual biomolecules and is non-ergodic over the time span ~10-12 to 102 seconds. Analysis of MD trajectories reveals that observed heterogeneity derives from the high-dimensional complex energy landscape. As the characteristic time for the protein to conduct its dephosphorylation function is ~10s seconds, these findings suggest that, due to non-ergodicity individual, otherwise seemingly identical protein molecules can be dynamically and functionally different. |
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