Bulletin of the American Physical Society
APS March Meeting 2020
Volume 65, Number 1
Monday–Friday, March 2–6, 2020; Denver, Colorado
Session B20: Physics of Proteins: Progress on Structure-Function Relationships IIFocus
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Sponsoring Units: DBIO DCOMP Chair: Wouter Hoff, Oklahoma State University-Stillwater Room: 301 |
Monday, March 2, 2020 11:15AM - 11:51AM |
B20.00001: The Incredible Secret Electronic Life of Proteins Invited Speaker: Stuart Lindsay Proteins are commonly believed to be insulators, consistent with their appearance and the results of simple measurements. This is in line with the expected behavior of a disordered, wide bandgap solid with strong vibronic coupling. Yet some soil bacteria transfer electrons via thin protein filaments with near-metallic conductivities. Are they a special case? Motivated by calculations that indicate that many proteins have evolved towards a quantum critical structure1 we decided to measure the conductance of single molecules of proteins chosen precisely because they lack redox centers and lack any known electron transfer function. Unique to our approach is the use of specific chemical bonding between proteins and electrodes to minimize the effects of contact resistance.2 We find that nS conductances over distances of many nm are common. The conductance is limited by contacts, with very long electronic decay lengths inside the protien.3 What biological pressure could drive evolution towards this unlikely state? We have studied a functioning DNA polymerase, finding large changes in its internal conductance as it undergoes functional changes in conformation. This suggests a possible role for delocalized states in function. It also points to a new method for DNA sequencing based on direct electrical measurement of enzyme function.4 |
Monday, March 2, 2020 11:51AM - 12:27PM |
B20.00002: Time-resolved Infrared Structural Biology of Proteins: Bringing New Light to Protein Structural Dynamics and Function Invited Speaker: Aihua Xie Nearly 150,000 of protein structures have been reported using X-ray crystallography, NMR technologies, and more recently cryogenic electron microscopy (Cryo-EM). Many of these structures played indispensable roles in our understanding of protein function. Then why do we need time-resolved infrared structural biology for proteins? Infrared structural biology is an emerging technology that offers unique advantages. Based on the 3D structure of a protein, can the functional mechanism of this protein be fully explained? In my talk, I will discuss important challenges we are facing in protein structural biology, and how to overcome some of these challenges using time-resolved infrared structural biology of proteins. More importantly, time-resolved infrared structural biology can bring new insight to the study of many proteins. |
Monday, March 2, 2020 12:27PM - 12:39PM |
B20.00003: Domain Swapping in Crystallin Proteins Can Drive Early Stages of Cataract Formation Govardhan Patluri Crystallins (Crys) are densely packed, long-lived eye lens proteins responsible for the ocular functions of the lens. Physicochemical perturbations in the cellular environment disrupt the native state stability of Cry proteins and populate aggregation prone misfolded states. These misfolded states gradually accumulate to produce high molecular weight amorphous aggregates, which scatter visible light resulting in lens opacity or cataract. The molecular mechanism of cataract formation or structure of these aggregation prone precursors remain elusive to date. Using molecular dynamics simulations and coarse-grained protein model of human γC and γD Crys, we identified the aggregation prone misfolded states present in the unfolding pathways of these proteins. We further show that these partially misfolded conformations readily undergo dimerization by domain swapping revealing the early stages of aggregation leading to cataract formation. |
Monday, March 2, 2020 12:39PM - 12:51PM |
B20.00004: Evaluating molecular simulations of protein dynamics using novel experimental data Lauren McGough, Justin Kim, Eugene Klyshko, Rama Ranganathan, Sarah Rauscher Proteins are evolved molecular machines that carry out the essential chemical reactions necessary for life. Like machines designed by humans, proteins execute their functions through an orderly set of motions and fluctuations - their “reaction coordinate”. However, proteins are also marginally stable, with the expectation that functional dynamics are embedded in a small subspace of a high dimensional pattern of overall motions and configurational changes. One approach to studying intramolecular fluctuations is computational simulation of atomic trajectories using molecular dynamics. Recent advances in experimental protein dynamics now open up the ability to test, validate, and possibly improve the process of molecular dynamics (MD) simulations through direct comparisons between computational predictions and data. We present a comparative analysis between MD and experiment using data from X-ray diffraction studies reporting electric field-stimulated excited state motions. The analysis develops methods for simulating a protein crystal while carrying out rigorous evaluations of structural conformation ensembles, atomic strain, force field differences, and more. This work represents an opportunity for MD and initiates a path towards understanding the physics of protein function. |
Monday, March 2, 2020 12:51PM - 1:03PM |
B20.00005: Effects of artificial mutations on topological features of proteins Haru Negami Relationship between the mutations of the proteins and its physiological activities is an important research area for many reasons. One reason is that bacteria or viruses acquire their resistance to existing drugs by mutations. The conformational changes due to the mutations have a significant role on the affinitiy to their ligand. |
Monday, March 2, 2020 1:03PM - 1:15PM |
B20.00006: Using Molecular Dynamics to Improve Molecular Docking Connor Morris, Dennis Della Corte We have been developing an improved method of protein-ligand docking. In our study of an intrinsically disordered protein, SNAP25B, we discovered that docking on a single rigid protein structure alone does not give us complete information on how the protein-ligand pair would interact in vivo, since intrinsically disordered proteins can form multiple 3D structures. A docking-predicted binding pose on this rigid structure may not exist in vivo due to the tendency of the 3D structure of the protein to change under different conditions. However, running the protein through a molecular dynamics (MD) simulation and collecting multiple 3D protein structures gives information about how the protein structure changes in solution. Docking on these MD-derived 3D protein structures increases the probability of finding an accurate ligand binding position using molecular docking that matches in vivo interactions. |
Monday, March 2, 2020 1:15PM - 1:27PM |
B20.00007: Marburg VP24 Protein K-loop Cysteine Interactions with the Human Keap1 Protein Nisha Bhattarai, Bernard S Gerstman, Prem P Chapagain Marburg and Ebola viruses are pathogenic viruses that belong to the Filovirus family and have up to 90% fatality rates. The Marburg VP24 protein (mVP24), has been found to bind with the Human Keap1 protein, which allows the nuclear accumulation of Nrf2, activating the antioxidant response elements during the viral life cycle. In this work, we investigate the molecular level details of the interactions between Marburg and Ebola VP24 proteins and Keap1 using molecular dynamics simulation. Sequence alignment of Ebola and Marburg VP24 reveals that two cysteine residues are present in mVP24 protein but absent in the Ebola VP24 protein (eVP24). Our results show that the presence of cysteine residues in the K-loop region of Marburg VP24 protein makes binding with Keap1 stronger, forming hydrogen bonding and pi-interactions. These cysteine residues are absent in eVP24 protein, which does not bind with Keap1. These computational results provide insights into how Marburg but not Ebola, is able to bind with Keap1 protein and activate antioxidant response pathways. |
Monday, March 2, 2020 1:27PM - 1:39PM |
B20.00008: Anomalous kinetics on low-fouling surfaces Diego Krapf, Mohammadhasan Hedayati, Matt J Kipper Protein-surface interactions were probed in terms of adsorption and desorption on a low-fouling surface using single-molecule localization microscopy. Strikingly the experimental data show anomalous kinetics, evident as a surface dwell time distribution that exhibits a power-law distribution, i.e. a heavy-tailed rather than an exponential distribution. As a consequence, the average desorption rate depends upon the time scale of the experiment and the surface protein concentration does not reach equilibrium. Further analysis reveals that the observed anomalous desorption emerges due to the reversible formation of a small fraction of soluble protein multimers, such that each one desorbs from the surface at a different rate. The overall kinetics can be described by a series of elementary reactions, yielding simple scaling relations that predict experimental observations. This work reveals a mechanistic origin for anomalous adsorption/desorption kinetics that can be employed to define design principles for non-fouling surfaces and to predict their performance. |
Monday, March 2, 2020 1:39PM - 1:51PM |
B20.00009: Single polypeptide antibody functionalized electrochemical probe development for enterovirus detection Yi-Xiang Lu, Chia-Yu Chang, Wen-Bin Fan, Jyh-Yuan Yang, Chia-Ching Chang Enterovirus 71 affects global public health and causes the millions of infections in human via oral and respiratory infection every year. Conventional detection approaches are through cell culture and PCR assay processes. However, these processes are time consuming. Therefore, a rapid, sensitive detection of enterovirus is required. Electrochemical impedance spectroscopy (EIS) is widely used for antigen-antibody interaction to measure the impedance change of the bio-sensing probe. However, conventional antibody is not stable for EIS probe. We have developed a single polypeptide antibody for enterovirus 71 detection. This single polypeptide antibody can conjugate with EIS electrode directly via self-assembly process. Moreover, this functionalized sensing probe can bind with EV71 sensitively and selectively within a few minutes by EIS. This single polypeptide antibody is relatively stable to detect enterovirus and may reduce the risk of enterovirus outbreak. |
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