Bulletin of the American Physical Society
APS March Meeting 2019
Volume 64, Number 2
Monday–Friday, March 4–8, 2019; Boston, Massachusetts
Session Y64: Physics of Proteins and Nucleic Acids II: Structures, Dynamics, Interactions, and EnergeticsFocus
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Sponsoring Units: DBIO DPOLY Chair: Aihua Xie, Oklahoma State Univ Room: BCEC 259B |
Friday, March 8, 2019 11:15AM - 11:51AM |
Y64.00001: The physical basis of computer-aided drug design: assessing and advancing the accuracy of binding affinity calculations Invited Speaker: Michael Gilson Predicting the binding thermodynamics of proteins and small organic molecules is a key aim in computer-aided drug design. I will provide an introduction to this problem in physical chemistry, the statistical mechanical framework for models of binding, and computational approaches based on this framework. I will then describe some interesting and unexpected outcomes of blinded prediction challenges in this field and what they indicate about steps required to improve accuracy, notably the need for improve potential functions, also known as force fields. Finally, I'll present the approaches we are taking, in coordination with the Open Force Field Initiative, to improve the accuracy of force fields and thus speed the discovery of new medications. |
Friday, March 8, 2019 11:51AM - 12:27PM |
Y64.00002: New strategies to predict protein-peptide interactions Invited Speaker: Xiaoqin Zou
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Friday, March 8, 2019 12:27PM - 12:39PM |
Y64.00003: Effects of Small Compounds on Structure of Amyloid-β1-42 Monomer Farbod Mahmoudinobar, Zhaoqian Su, Cristiano Dias Alzheimer’s disease is associated with deposits of Amyloid-β, an intrinsically disordered peptide. Molecular structure and aggregation rate of Aβ are observed to be significantly dependent on the properties of its aqueous environment. For example, NaCl is shown to accelerate Aβ fibril formation whereas 4-Aminophenol (4AP) and Inositol have been shown to reduce its aggregation rate. Despite many studies to investigate the effects of small molecules on aggregation of Aβ, its atomic interactions with small molecules that mediate various structures and behavior of this peptide are not well understood. To investigate Aβ molecular structures and to understand how Aβ properties are affected by compounds, we performed extensive Replica Exchange Molecular Dynamics (REMD) simulations on Aβ1-42 monomer with explicit solvent and small molecules. Our research reveals that each molecule affects different regions of Aβ1-42 and the peptide adopts distinguished structures compared to control system. Specifically, we observe that NaCl increases contact among residues K16-E22 and V38-I41 while 4AP increases K16-E22 and N27-G37 contacts and Inositol mainly disrupts the intrapeptide contacts. Effects of compounds on structural and physical properties of Aβ1-42 monomer will also be discussed. |
Friday, March 8, 2019 12:39PM - 12:51PM |
Y64.00004: Cluster-expansion theory for sequence-specific "fuzzy” interaction between a pair of intrinsically disordered proteins Alan Amin, Yi-Hsuan Lin, Suman Das, Hue Sun Chan Intrinsically disordered proteins (IDPs) do not fold into a unique tertiary structure in isolation, likely because they are depleted in hydrophobic but enriched in polar, charged, and aromatic amino acids. While many IDPs become ordered upon binding to folded proteins, several IDPs have been recently discovered to retain their structural disorder when binding with each other via a so-called "fuzzy" mechanism. Just like interactions between folded proteins, such a fuzzy mechanism must be determined by the amino acid sequences of the IDPs. Here, we implement the cluster expansion method in statistical mechanics to develop an analytical theory for calculating the sequence-specific IDP-IDP binding affinity. We apply the theory to various IDP pairs selected from a set of 30 polyampholytic IDP sequences with the same amino acid composition but different charge patterns. The sequence-specific correlation between the double-chain binding affinities and single-chain conformations are systematically investigated. Our analytical theory provides a concise and powerful tool for high-throughput proteomic analysis of IDP-IDP interaction. |
Friday, March 8, 2019 12:51PM - 1:03PM |
Y64.00005: Conformation-Induced Conductivity Switching in Bacterial Protein Nanowires Sibel Ebru Yalcin, J. Patrick O'brien, Atanu Acharya, Yangqi Gu, Peter Dahl, Sophia Yi, Winston Huynh, Subhajyoti Chaudhuri, Victor Batista, Nikhil Malvankar Large-scale conformational changes in molecules are attractive because they can serve as information carriers for switches in memory and logic devices. Here we report the ability to control molecular conductivity via conformational switching at an unprecedented scale. Atomic force microscopy showed that individual Geobacter sulfurreducens protein nanowires undergo > 20 Å conformational change that propagates over their micrometer-lengths upon changing the environment. This increases the mechanical stiffness of nanowires by 4-fold and dc conductivity by 15,000-fold. Infrared nanospectroscopy revealed that this conformational change is driven by an internal structural transition. A suite of complementary experimental and computational methods such as X-ray diffraction, Raman, UV-Vis, fluorescence emission spectroscopy and circular dichroism further demonstrated this structural transition. Our studies thus establish nanoscopic approaches to visualize and quantify large-scale conformational changes in biomolecules and present novel strategies for tuning their structure and conductivity. Our work will guide the creation of a new class of programmable biomaterials with precisely controlled electronic and mechanical properties. |
Friday, March 8, 2019 1:03PM - 1:15PM |
Y64.00006: Computational Protein Redesign and Decoy Discrimination Zhe Mei, John Treado, Zachary Levine, Corey Shane O'Hern, Lynne Regan A key aim of computational protein design is to understand how amino acid mutations affect the structure and stability of proteins. Recent studies have used molecular dynamics (MD) simulations to predict the response of wildtype proteins to mutations. However, MD structures can be trapped in local free energy basins, resulting in configurations that diverge significantly from experimental crystal structures. In this work, we construct a mutation dataset, which contains 32 pairs of single-core-residue mutated crystal structures and their corresponding wildtype structures. We perform replica-exchange MD (REMD) simulations on wildtype and mutant structures to obtain a series of possible protein conformations before and after the core mutations. We then perform residue repacking to determine whether the side chain conformations match these in the crystal structures. We also evaluate the local packing fraction and void geometry of the protein structures from REMD simulations to distinguish decoys from the crystal structures. The ability to distinguish experimental structures from decoys will enable unprecedented validation of MD simulations, and provide insight into novel structures that have not yet been experimentally characterized. |
Friday, March 8, 2019 1:15PM - 1:27PM |
Y64.00007: Weighted ensemble simulations of biomolecules: Applications to peptides and proteins Hiroshi Fujisaki, Kei Moritsugu, Ayori Mitsutake, Hiromichi Suetani Weighted ensemble (WE) method is an efficient way to numerically sample rare event trajectories generated by random dynamical systems, first introduced by Huber and Kim [1] and further extended by Zuckerman and coworkers [2]. |
Friday, March 8, 2019 1:27PM - 1:39PM |
Y64.00008: Identifying Trimerization Mechanisms of Human Islet Amyloid Polypeptide through Molecular Simulation Ashley Guo, Juan De Pablo Human islet amyloid polypeptide (hIAPP, or human amylin) is implicated in the development of type II diabetes and is known to aggregate into amyloid fibrils. Early-stage aggregates have been shown to be cytotoxic, prompting study of prefibrillar oligomeric species and their aggregation mechanisms. Here, we build upon recent work that studied formation of the hIAPP dimer, which identified a dimerization pathway and its corresponding free energy profile, by studying and comparing hIAPP trimerization mechanisms. We use atomistic molecular dynamics simulations combined with the finite-temperature string method to identify favorable pathways for trimer formation, relevant intermediate structures, and free energy changes during trimerization. Specifically, we compare and contrast two trimerization scenarios: (1) formation of a trimer from three disordered hIAPP molecules, and (2) formation of a trimer from a single disordered hIAPP molecule added to an hIAPP dimer. |
Friday, March 8, 2019 1:39PM - 1:51PM |
Y64.00009: Direct experimental characterization of contributions from self-motion of hydrogen and from interatomic motion of heavy atoms to protein anharmonicity Zhuo Liu, Chenxing Yang, Juan Huang, Jun Li One of challenges in biophysics is to understand the connection between protein dynamics and its function. The challenge partially arises from the fact that protein present a variety of local atomic motions and collective dynamics on the same time scales, and this has rendered difficult the experimental identification and quantification of different dynamic modes. Here, taking lyophilized protein as examples, we combined the deuteration technique and the neutron scattering experiment to separate the self-motion and the collective interatomic motion of heavy atoms in proteins. We found that the self-motions of protein hydrogen atoms present a resolution-time-dependent anharmonic onset, with the onset temperature increasing when decreasing the resolution time. This can be ascribed to the thermal activation of local side-group motions, mostly the methyl rotations. In contrast, the collective dynamics of protein heavy atoms exhibit a resolution-time-independent anharmonicity around 200 K. Further dielectric spectroscopy and Brillouin light scattering results suggest that the anharmonicity of the heavy atoms results from unfreezing of the relaxation of the protein structures on the laboratory equilibrium time (100-1000 s), which softens the entire bio-macromolecules. |
Friday, March 8, 2019 1:51PM - 2:03PM |
Y64.00010: ABSTRACT WITHDRAWN
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Friday, March 8, 2019 2:03PM - 2:15PM |
Y64.00011: Topological analysis of morphological changes of proteins due to the differences of experimental conditions of X-ray structural analysis Haru Negami In structural biology, it is an important problem how tiny local mutation of the protein affect its global structure. To understand the mechanism, we focus on a topological method called “Fatgraph models of proteins” [1]. The model is a topological two-manifold with boundary components (surface) which have one to one correspondence with three-dimensional protein structures listed on Protein Data Bank (PDB) [2] with several exceptions. The traits of each surface for each protein are described by invariants. |
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