Bulletin of the American Physical Society
APS March Meeting 2019
Volume 64, Number 2
Monday–Friday, March 4–8, 2019; Boston, Massachusetts
Session R63: Physics of Proteins and Nucleic Acids I: Structures, Dynamics, Interactions, and EnergeticsFocus
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Sponsoring Units: DBIO DPOLY Chair: Huan-Xiang Zhou, Florida State University Room: BCEC 259A |
Thursday, March 7, 2019 8:00AM - 8:36AM |
R63.00001: Single molecule measurements provide insight into general secretory system activity Invited Speaker: Gavin King How are proteins transported across membranes? The general secretory (Sec) system of E. coli exports precursor proteins via a translocase comprising the peripheral ATPase SecA and the translocon, SecYEG. Structural changes of active translocases underlie the translocation process. Yet, the mechanistic details of this complex and dynamic system have proven challenging to study. The atomic force microscope (AFM) is well suited for imaging membrane proteins in near-native conditions and can achieve molecular-scale (~10 Å) lateral resolution coupled with ~1 Å vertical resolution (i.e., normal to the bilayer surface). We imaged individual components of the Sec system as well as active translocases at work in lipid bilayers. In this talk I will review our single molecule results in the context of conventional models in the field, which are based on bulk assays. In addition to imaging, AFM can be used in force spectroscopy mode, providing access to energy landscapes. Our group has applied precision AFM-based force spectroscopy techniques to study a peptide-lipid interaction underlying Sec system activity. Together with analytical modeling and simulations, the results represent a step towards a more detailed understanding of the protein export process in E. coli, and more generally, of the stochastic kinetic pathways driving peptide-lipid interactions. |
Thursday, March 7, 2019 8:36AM - 8:48AM |
R63.00002: Mechanical determinants of protein function and evolution Sandipan Dutta, Tsvi Tlusty A common physical basis for the diverse biological functions of proteins is the emergence of collective patterns of forces and coordinated displacements of their amino acids. We will discuss a minimal model examining the effect of global motions and long-range interactions on protein functions that involve molecular information processing. |
Thursday, March 7, 2019 8:48AM - 9:00AM |
R63.00003: Protein Intramolecular Motions with Deuteration and Inhibitor Binding Dependence Yanting Deng, Jeffrey McKinney, Tod Romo, Alan Grossfield, Andrea Markelz Protein collective vibrations dynamically sample structural configurations enabling conformational change [1]. Recently these vibrations have been isolated by their direction of motion using anisotropic terahertz microscopy [2]. To assign structural displacements with the observed resonant absorption bands, we measure their changes with deuteration and inhibitor (3NAG) binding for lysozyme using triclinic crystals and compare these measurements to normal mode ensemble analysis (NMEA) [2]. The sample’s P1 crystal symmetry and quality were confirmed by X-ray after THz measurements with a = 28.5 Å, b = 32.7 Å, c = 35.1 Å, α = 88.2°, β = 108.9°, γ = 111.9°. The protonated, deuterated and 3NAG-bound triclinic crystals were measured using a new technique: ideal polarization varying anisotropic Terahertz microscopy. We compare the relative frequency shifts of the measured protonated and deuterated protein vibrations, and changes with inhibitor binding dependence to the calculated spectra averaged over >500 starting structures to make tentative assignments. |
Thursday, March 7, 2019 9:00AM - 9:12AM |
R63.00004: Optimality of cooperativity in allosteric materials and proteins Riccardo Ravasio, Solange Flatt, Le Yan, Stefano Zamuner, Carolina Brito, Matthieu Wyart Allostery is responsible for the activity regulation of many proteins essential for life. Many efforts on understanding this long-range communication have been made, but the physical picture of allosteric mechanics is not yet clear. Recent progress employing in-silico evolutions studied mechanical networks of harmonic springs with allosteric behaviors. These networks are found to share common principles for the long-range communication to occur. Specifically, the stiffness of the allosteric response scales with the system size with a nontrivial power law. In this work, we test these principles in real systems, using a large set of X-ray structural data of allosteric proteins. Overall, we find that the functional allosteric response of each protein is related to a “mechanism”, a soft and extended mode with strong strain. By extending the theory of allosteric materials to include nonlinearities, we identify two scalings of stiffness setting a regime where the allosteric cooperative binding is optimal. A new scaling exponent appears, in addition to the one from the linear theory. The stiffness from the X-ray structural data falls in this predicted range, suggesting that proteins actually work at optimal cooperativity. |
Thursday, March 7, 2019 9:12AM - 9:24AM |
R63.00005: Finding the Optimal Folding Routes of self-entangled Proteins via Coarse-Grained Molecular Dynamics Claudio Perego, Raffaello Potestio Among the known protein motifs, several structures exhibit a self-entangled backbone topology. Understanding how polypeptides can efficiently and reproducibly attain such topologies is a crucial biophysical challenge, which might shed new light on our general understanding of protein folding. |
Thursday, March 7, 2019 9:24AM - 9:36AM |
R63.00006: Molecular mechanisms for protein-denaturation in urea and guanidinium chloride mixtures Pritam Ganguly, Joan-Emma Shea Using replica-exchange molecular dynamics simulations, we have studied the thermodynamic stability and the conformational changes of two synthetic mini-proteins, Trp-cage and Trp-zip1, in pure and mixed denaturant solutions of guanidinium chloride (GdmCl) and urea. We have found that urea, which denatures proteins through favorable preferential interactions with protein sidechains and backbone, is more effective in destabilizing and elongating alpha-helical secondary structures of proteins than beta-hairpin structures. Contrarily, GdmCl, which denatures proteins by inhibiting salt-bridge formations between charged amino acids, is more effective in destabilizing beta-hairpin structures than alpha-helical structures. The extent of GdmCl-induced protein-denaturation is not determined by protein-GdmCl preferential interactions. In mixed denaturant conditions, our results indicate that GdmCl may however enhance the overall denaturing effects of urea by promoting protein-urea preferential interactions when full-length proteins are considered, but it may also potentially lead to local compaction of smaller segments of proteins, partially counteracting urea-induced extension of the protein segments. |
Thursday, March 7, 2019 9:36AM - 9:48AM |
R63.00007: Large-scale, automated prediction of protein-ligand binding structures Zhiwei Ma, Xianjin Xu, Rui Duan, Xiaoqin Zou Molecular docking is a useful and important approach for the prediction of protein-ligand structures and for structure-based drug design. The growing number of protein-ligand complex structures, particularly the structures of proteins co-bound with different ligands, in the Protein Data Bank helps us tackle two major challenges in molecular docking studies: the protein flexibility and the energy scoring function. Here, we introduced a systematic strategy by using the information embedded in the known protein-ligand complex structures to improve binding mode predictions. We also developed and integrated several methods for large-scale binding mode prediction, and systematically tested these methods on the weekly Continuous Evaluation of Ligand Pose Prediction (CELPP) competition, an automated workflow to process and evaluate the challenge of ligand pose prediction. Up to October 26, 2018, the quantitative analysis of our docking results for over 3000 targets released by CELPP revealed that our methods improve the success rates of ligand pose prediction. |
Thursday, March 7, 2019 9:48AM - 10:00AM |
R63.00008: Inferring protein dynamics through experiment and simulation: collective modes from atomic trajectories Lauren McGough, Rama Ranganathan 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 small subspace of a high dimensional pattern of overall motions. Here, we aim to discover the embedded functional dynamics using experiment and simulation. |
Thursday, March 7, 2019 10:00AM - 10:12AM |
R63.00009: Temperature dependent studies of proteins and their hydration shell properties using megahertz-to-terahertz dielectric spectroscopy Ali Charkhesht, Djamila Lou, Ben Sindle, Vinh Q Nguyen The low-frequency collective vibrational modes in proteins and the protein–water interface playing an important role in biochemical reactions and biological energy transport strongly depend on the temperature and conditions of the environment. However, capturing a precise picture of collective vibrational dynamics under temperature variations is challenging due to the strong absorption of water. For this reason, we have employed a highly sensitive dielectric megahertz-to-terahertz frequency-domain system to probe the vibrational dynamics of proteins in aqueous solutions from 50 MHz to 2 THz. With this approach, we have performed an exclusive temperature dependent study on myoglobin and lysozyme in water by means of complex dielectric analysis. We have focused on protein collective vibrational processes and atypical surrounding water molecules to outline comprehensive images of aqueous solutions. The results help us to clarify protein dynamics and protein-water interfaces in temperature dependent environment that determine biochemical functions and reactivity of proteins. |
Thursday, March 7, 2019 10:12AM - 10:24AM |
R63.00010: Protein Structural Fluctuations at Criticality in the Temperature-pressure-crowding Folding Phase Diagram Andrei G Gasic, Caleb M Daugherty, Margaret Cheung In the cell, proteins perform complex biological functions through large-scale motion, which are induced by slight environmental perturbations. This characteristic of having high susceptibility is similar to a physical system near a critical point. Indeed, recent experimental and computational findings demonstrate that protein folding transitions in the temperature (T), pressure (P), and crowding volume-fraction (φc) phase diagram point toward signatures of criticality, where distinct folding phases merge. Here, using coarse-grained molecular dynamics simulations, we theoretically show that at the critical regime, fluctuations exhibit high susceptibility and long-range correlations up to the size of the protein. Meaning that near criticality, the dynamics of each residue is influenced by each other residue even across the entire protein. We investigate the structural origin and the effect of macromolecular crowding on this critical behavior. Furthermore, this study leads us one step closer to developing universal principles of protein folding and function in vivo. |
Thursday, March 7, 2019 10:24AM - 10:36AM |
R63.00011: Neighbourhood preference based energy function and its applications in structure prediction and protein evolution siyuan liu, xilun xiang, Haiguang Liu Based on the statistics from known structures in the protein data bank, a statistical energy function is derived to reflect the amino acid neighbourhood preferences. The neighbourhood of one amino acid is defined by its contacting residues, and the energy function is determined by the neighbhoring residue types and relative positions. A scoring function, Nepre, has been implemented and its performance was tested with several decoy sets. The results show that the Nepre program can be applied in model ranking to improve the success rate in structure predictions. We also applied this empirical energy function in the understanding of protein evolution and the designability of protein structures. |
Thursday, March 7, 2019 10:36AM - 10:48AM |
R63.00012: Protein Structure Prediction with MELD x MD James Robertson, Alberto Perez, Ken Dill Predicting protein structures from their amino acid sequences is a major challenge, especially with atomistic molecular dynamics (MD) simulations. The two major limitations to MD are poor sampling due to high computational cost and inaccurate force fields. Bioinformatics-based methods are an alternative approach to structure prediction that rely on databases of structures or structural fragments, as in threading. Threading has been very successful in predicting protein structures, but about 15% of proteins are not amenable to threading, the so-called nonthreadables. The nonthreadables provide a test set for MELD x MD, which does not rely on bioinformatics databases. We show that MELD x MD accurately predicts 20/41 nonthreadables and give high Boltzmann populations for successful predictions. We also discuss MELD x MD structure prediction on a larger set of proteins, particularly how the method is limited by sampling and force fields, but also how MELD x MD can overcome these limitations. |
Thursday, March 7, 2019 10:48AM - 11:00AM |
R63.00013: Dynamic Allosteric Residue Coupling (darc) Spots Shed Light on Functional Changes from Sequence Variation Paul Campitelli, Liskin Swint-Kruse, Banu Ozkan Defining the functional impact of protein sequence variation presents a major challenge in biology and genomics and the importance has grown dramatically as unprecedented advances in sequencing complete exomes have yielded tens of thousands of non-synonymous single nucleotide variants (nSNVs) on the human proteome. Currently there are no consistent methods to capture the mechanisms of functional changes as a result of sequence variations, particularly at non-conserved positions and in the absence of large structural changes. We present the dynamic flexibility index (dfi), a measure of residue-specific flexibility and the dynamic coupling index (dci), a technique determining coupling strength between amino acids. We apply our approach to the lactose repressor protein LacI, where substitutions at non-conserved position V52 produce progressive effects on function. dfi captures changes in flexibility in the DNA binding domain and is correlated with binding affinity. We also use dci to identify important dynamic allosteric residue coupling (darc) spots, distally located to the DNA binding domain. darc spot dfi correlates strongly with changes in repression rate as well as DNA binding affinity and shows conformational dynamics at distal sites plays an important role in LacI function. |
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