Protein Tertiary Structure and the Myoglobin Phase Diagram Alexander Begun1, Alexander Molochkov1 & Antti J
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Fast Pressure-Jump All-Atom Simulations and Experiments Reveal Site-Specific Protein Dehydration-Folding Dynamics
Fast pressure-jump all-atom simulations and experiments reveal site-specific protein dehydration-folding dynamics Maxim B. Prigozhina,1,2, Yi Zhangb,1, Klaus Schultenb,c, Martin Gruebelea,b,c,3, and Taras V. Pogorelova,b,d,e,3 aDepartment of Chemistry, University of Illinois at Urbana–Champaign, Urbana, IL 61801; bBeckman Institute for Advanced Science and Technology, Center for Biophysics and Quantitative Biology, University of Illinois at Urbana–Champaign, Urbana, IL 61801; cDepartment of Physics, University of Illinois at Urbana–Champaign, Urbana, IL 61801; dNational Center for Supercomputing Applications, University of Illinois at Urbana–Champaign, Urbana, IL 61801; and eSchool of Chemical Sciences, University of Illinois at Urbana–Champaign, Urbana, IL 61801 Edited by José N. Onuchic, Rice University, Houston, TX, and approved February 8, 2019 (received for review August 30, 2018) As theory and experiment have shown, protein dehydration is a and simulated using MD (18). Desolvated cavities in the protein major contributor to protein folding. Dehydration upon folding core (15) are restored by downward pressure jumps, which fa- can be characterized directly by all-atom simulations of fast cilitate refolding without a change in solvent or thermal motion. pressure drops, which create desolvated pockets inside the In addition, pressure perturbation reduces the effects of protein nascent hydrophobic core. Here, we study pressure-drop refolding aggregation, common in temperature-jump (T-jump) experi- of three λ-repressor fragment (λ6–85) mutants computationally and ments performed near the denaturation temperature (16, 17). experimentally. The three mutants report on tertiary structure for- Finally, pressure-jump (P-jump) experiments can utilize intrinsic mation via different fluorescent helix–helix contact pairs. -
Structural Mechanisms of Oligomer and Amyloid Fibril Formation by the Prion Protein Cite This: Chem
ChemComm View Article Online FEATURE ARTICLE View Journal | View Issue Structural mechanisms of oligomer and amyloid fibril formation by the prion protein Cite this: Chem. Commun., 2018, 54,6230 Ishita Sengupta a and Jayant B. Udgaonkar *b Misfolding and aggregation of the prion protein is responsible for multiple neurodegenerative diseases. Works from several laboratories on folding of both the WT and multiple pathogenic mutant variants of the prion protein have identified several structurally dissimilar intermediates, which might be potential precursors to misfolding and aggregation. The misfolded aggregates themselves are morphologically distinct, critically dependent on the solution conditions under which they are prepared, but always b-sheet rich. Despite the lack of an atomic resolution structure of the infectious pathogenic agent in prion diseases, several low resolution models have identified the b-sheet rich core of the aggregates formed in vitro, to lie in the a2–a3 subdomain of the prion protein, albeit with local stabilities that vary Received 17th April 2018, with the type of aggregate. This feature article describes recent advances in the investigation of in vitro Accepted 14th May 2018 prion protein aggregation using multiple spectroscopic probes, with particular focus on (1) identifying DOI: 10.1039/c8cc03053g aggregation-prone conformations of the monomeric protein, (2) conditions which trigger misfolding and oligomerization, (3) the mechanism of misfolding and aggregation, and (4) the structure of the misfolded rsc.li/chemcomm intermediates and final aggregates. 1. Introduction The prion protein can exist in two distinct structural isoforms: a National Centre for Biological Sciences, Tata Institute of Fundamental Research, PrPC and PrPSc. -
Molten-Globule’ State Accumulates in Carbonic Anhydrase Folding
View metadata, citation and similar papers at core.ac.uk brought to you by CORE provided by Elsevier - Publisher Connector Volume 165, number 1 FEBS 1079 January 1984 ‘Molten-globule’ state accumulates in carbonic anhydrase folding D.A. Dolgikh, A.P. Kolomiets, I.A. Bolotina* and O.B. Ptitsyn+ Institute of Protein Research, USSR Academy of Sciences, 142292 Pushchino, Moscow Region and *Institute of Molecular Biology, USSR Academy of Sciences, II 7312 Moscow, USSR Received 17 October 1983 Kinetics of folding and unfolding of bovine carbonic anhydrase B were monitored by circular dichroism, viscometry and esterase activity. It was shown that kinetic intermediate states accumulating in folding process reveal a native-like compactness and secondary structure but have a symmetrized average environment of aromatic side groups and no esterase activity. These properties allow one to consider these intermediate states as the ‘molten-globule’ state of a protein molecule previously described by us for several equilibrium forms of bovine and human Lu-lactalbumins and bovine carbonic anhydrase B. Carbonic anhydrase B Protein folding Molten-globule state of protein molecules Folding intermediate 1, INTRODUCTION this model the increase of fluctuations is due to a slight increase of the molecular volume leading to Recently [l-3] we have described a new equilib- a sharp decrease of Van der Waals intramolecular rium state of a protein molecule, ‘compact globular interactions [4]. state with fluctuating tertiary structure’, using the Quite recently we have found that a similar in- examples of bovine and human a-lactalbumins. termediate state also exists in bovine carbonic an- Both proteins can be transformed into this state hydrase B at pH -3.6 [3,5]. -
Native-Like Mean Structure in the Unfolded Ensemble of Small Proteins
B doi:10.1016/S0022-2836(02)00888-4 available online at http://www.idealibrary.com on w J. Mol. Biol. (2002) 323, 153–164 Native-like Mean Structure in the Unfolded Ensemble of Small Proteins Bojan Zagrovic1, Christopher D. Snow1, Siraj Khaliq2 Michael R. Shirts2 and Vijay S. Pande1,2* 1Biophysics Program The nature of the unfolded state plays a great role in our understanding of Stanford University, Stanford proteins. However, accurately studying the unfolded state with computer CA 94305-5080, USA simulation is difficult, due to its complexity and the great deal of sampling required. Using a supercluster of over 10,000 processors we 2Department of Chemistry have performed close to 800 ms of molecular dynamics simulation in Stanford University, Stanford atomistic detail of the folded and unfolded states of three polypeptides CA 94305-5080, USA from a range of structural classes: the all-alpha villin headpiece molecule, the beta hairpin tryptophan zipper, and a designed alpha-beta zinc finger mimic. A comparison between the folded and the unfolded ensembles reveals that, even though virtually none of the individual members of the unfolded ensemble exhibits native-like features, the mean unfolded structure (averaged over the entire unfolded ensemble) has a native-like geometry. This suggests several novel implications for protein folding and structure prediction as well as new interpretations for experiments which find structure in ensemble-averaged measurements. q 2002 Elsevier Science Ltd. All rights reserved Keywords: mean-structure hypothesis; unfolded state of proteins; *Corresponding author distributed computing; conformational averaging Introduction under folding conditions, with some notable exceptions.14 – 16 This is understandable since under Historically, the unfolded state of proteins has such conditions the unfolded state is an unstable, received significantly less attention than the folded fleeting species making any kind of quantitative state.1 The reasons for this are primarily its struc- experimental measurement very difficult. -
Studying Backbone Torsional Dynamics of Intrinsically Disordered Proteins Using fluorescence Depolarization Kinetics
J Biosci Vol. 43, No. 3, July 2018, pp. 455–462 Ó Indian Academy of Sciences DOI: 10.1007/s12038-018-9766-1 Studying backbone torsional dynamics of intrinsically disordered proteins using fluorescence depolarization kinetics 1,3 1,2,3 DEBAPRIYA DAS and SAMRAT MUKHOPADHYAY * 1Centre for Protein Science, Design and Engineering, Indian Institute of Science Education and Research (IISER) Mohali, Punjab, India 2Department of Biological Sciences, Indian Institute of Science Education and Research (IISER) Mohali, Punjab, India 3Department of Chemical Sciences, Indian Institute of Science Education and Research (IISER) Mohali, Punjab, India *Corresponding author (Email, [email protected]) Published online: 7 June 2018 Intrinsically disordered proteins (IDPs) do not autonomously adopt a stable unique 3D structure and exist as an ensemble of rapidly interconverting structures. They are characterized by significant conformational plasticity and are associated with several biological functions and dysfunctions. The rapid conformational fluctuation is governed by the backbone segmental dynamics arising due to the dihedral angle fluctuation on the Ramachandran /–w conformational space. We discovered that the intrinsic backbone torsional mobility can be monitored by a sensitive fluorescence readout, namely fluorescence depolarization kinetics, of tryptophan in an archetypal IDP such as a-synuclein. This methodology allows us to map the site-specific torsional mobility in the dihedral space within picosecond-nanosecond time range at a low protein concen- tration under the native condition. The characteristic timescale of * 1.4 ns, independent of residue position, represents collective torsional dynamics of dihedral angles (/ and w) of several residues from tryptophan and is independent of overall global tumbling of the protein. -
Linking Predictions of Protein Structure and Disorder Through Molecular Simulation
The Order-Disorder Continuum: Linking Predictions of Protein Structure and Disorder through Molecular Simulation The MIT Faculty has made this article openly available. Please share how this access benefits you. Your story matters. Citation Hsu, Claire C., Markus J. Buehler, and Anna Tarakanova. "The Order-Disorder Continuum: Linking Predictions of Protein Structure and Disorder through Molecular Simulation." Scientific Reports, 10 (February 2020): 2068. © 2020, The Author(s). As Published http://dx.doi.org/10.1038/s41598-020-58868-w Publisher Springer Science and Business Media LLC Citable link https://hdl.handle.net/1721.1/125166 Terms of Use Creative Commons Attribution 4.0 International license Detailed Terms https://creativecommons.org/licenses/by/4.0/ www.nature.com/scientificreports OPEN The Order-Disorder Continuum: Linking Predictions of Protein Structure and Disorder through Molecular Simulation Claire C. Hsu1, Markus J. Buehler2 & Anna Tarakanova3,4* Intrinsically disordered proteins (IDPs) and intrinsically disordered regions within proteins (IDRs) serve an increasingly expansive list of biological functions, including regulation of transcription and translation, protein phosphorylation, cellular signal transduction, as well as mechanical roles. The strong link between protein function and disorder motivates a deeper fundamental characterization of IDPs and IDRs for discovering new functions and relevant mechanisms. We review recent advances in experimental techniques that have improved identifcation of disordered regions -
The Conformation of Serum Albumin in Solution: a Combined Phosphorescence Depolarization-Hydrodynamic Modeling Study
2422 Biophysical Journal Volume 80 May 2001 2422–2430 The Conformation of Serum Albumin in Solution: A Combined Phosphorescence Depolarization-Hydrodynamic Modeling Study M. Luisa Ferrer,* Ricardo Duchowicz,* Beatriz Carrasco,† Jose´ Garcı´a de la Torre,† and A. Ulises Acun˜a* *Instituto Quı´mica-Fı´sica “Rocasolano”, Consejo Superior de Investigaciones Cientificas, 28006 Madrid, and †Departamento de Quı´mica-Fı´sica, Universidad de Murcia, 30071 Murcia, Spain ABSTRACT There is a striking disparity between the heart-shaped structure of human serum albumin (HSA) observed in single crystals and the elongated ellipsoid model used for decades to interpret the protein solution hydrodynamics at neutral pH. These two contrasting views could be reconciled if the protein were flexible enough to change its conformation in solution from that found in the crystal. To investigate this possibility we recorded the rotational motions in real time of an erythrosin- bovine serum albumin complex (Er-BSA) over an extended time range, using phosphorescence depolarization techniques. These measurements are consistent with the absence of independent motions of large protein segments in solution, in the time range from nanoseconds to fractions of milliseconds, and give a single rotational correlation time (BSA, 1 cP, 20°C) ϭ 40 Ϯ 2 ns. In addition, we report a detailed analysis of the protein hydrodynamics based on two bead-modeling methods. In the first, BSA was modeled as a triangular prismatic shell with optimized dimensions of 84 ϫ 84 ϫ 84 ϫ 31.5 Å, whereas in the second, the atomic-level structure of HSA obtained from crystallographic data was used to build a much more refined rough-shell model. -
Numerical Evaluation of Protein Global Vibrations at Terahertz Frequencies by Means of Elastic Lattice Models †
Proceedings Numerical Evaluation of Protein Global Vibrations at Terahertz Frequencies by Means of Elastic † Lattice Models Domenico Scaramozzino *, Giuseppe Lacidogna, Gianfranco Piana and Alberto Carpinteri Department of Structural, Geotechnical and Building Engineering, Politecnico di Torino, Corso Duca degli Abruzzi 24, 10129 Torino, Italy; [email protected] (G.L.); [email protected] (G.P.); [email protected] (A.C.) * Correspondence: [email protected] † Presented at 1st International Electronic Conference on Applied Sciences, 10–30 November 2020; Available online: https://asec2020.sciforum.net/. Published: 9 November 2020 Abstract: Proteins represent one of the most important building blocks for most biological processes. Their biological mechanisms have been found to correlate significantly with their dynamics, which is commonly investigated through molecular dynamics (MD) simulations. However, important insights on protein dynamics and biological mechanisms have also been obtained via much simpler and computationally efficient calculations based on elastic lattice models (ELMs). The application of structural mechanics approaches, such as modal analysis, to the protein ELMs has allowed to find impressive results in terms of protein dynamics and vibrations. The low-frequency vibrations extracted from the protein ELM are usually found to occur within the terahertz (THz) frequency range and correlate fairly accurately with the observed functional motions. In this contribution, the global vibrations of lysozyme will be investigated by means of a finite element (FE) truss model, and we will show that there exists complete consistency between the proposed FE approach and one of the more well-known ELMs for protein dynamics, the anisotropic network model (ANM). The proposed truss model can consequently be seen as a simple method, easily accessible to the structural mechanics community members, to analyze protein vibrations and their connections with the biological activity. -
DNA Energy Landscapes Via Calorimetric Detection of Microstate Ensembles of Metastable Macrostates and Triplet Repeat Diseases
DNA energy landscapes via calorimetric detection of microstate ensembles of metastable macrostates and triplet repeat diseases Jens Vo¨ lkera, Horst H. Klumpb, and Kenneth J. Breslauera,c,1 aDepartment of Chemistry and Chemical Biology, Rutgers, The State University of New Jersey, 610 Taylor Rd, Piscataway, NJ 08854; bDepartment of Molecular and Cell Biology, University of Cape Town, Private Bag, Rondebosch 7800, South Africa; and cCancer Institute of New Jersey, New Brunswick, NJ 08901 Communicated by I. M. Gelfand, Rutgers, The State University of New Jersey, Piscataway, NJ, October 15, 2008 (received for review September 8, 2008) Biopolymers exhibit rough energy landscapes, thereby allowing biological role(s), if any, of kinetically stable (metastable) mi- biological processes to access a broad range of kinetic and ther- crostates that make up the time-averaged, native state ensembles modynamic states. In contrast to proteins, the energy landscapes of macroscopic nucleic acid states remains to be determined. of nucleic acids have been the subject of relatively few experimen- As part of an effort to address this deficiency, we report here tal investigations. In this study, we use calorimetric and spectro- experimental evidence for the presence of discrete microstates scopic observables to detect, resolve, and selectively enrich ener- in metastable triplet repeat bulge looped ⍀-DNAs of potential getically discrete ensembles of microstates within metastable DNA biological significance. The specific triplet repeat bulge looped structures. Our results are consistent with metastable, ‘‘native’’ ⍀-DNA species investigated mimic slipped DNA structures DNA states being composed of an ensemble of discrete and corresponding to intermediates in the processes that lead to kinetically stable microstates of differential stabilities, rather than DNA expansion in triplet repeat diseases (36). -
State Folding of Globular Proteins
Preprints (www.preprints.org) | NOT PEER-REVIEWED | Posted: 20 February 2020 doi:10.20944/preprints202002.0290.v1 Peer-reviewed version available at Biomolecules 2020, 10, 407; doi:10.3390/biom10030407 Review The Molten Globule, and Two-State vs. Non-Two- State Folding of Globular Proteins Kunihiro Kuwajima,* Department of Physics, School of Science, the University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-0033, Japan, and School of Computational Sciences, Korea Institute for Advanced Study (KIAS), Seoul 02455, Korea ; [email protected] * Correspondence: [email protected] Abstract: From experimental studies of protein folding, it is now clear that there are two types of folding behavior, i.e., two-state folding and non-two-state folding, and understanding the relationships between these apparently different folding behaviors is essential for fully elucidating the molecular mechanisms of protein folding. This article describes how the presence of the two types of folding behavior has been confirmed experimentally, and discusses the relationships between the two-state and the non-two-state folding reactions, on the basis of available data on the correlations of the folding rate constant with various structure-based properties, which are determined primarily by the backbone topology of proteins. Finally, a two-stage hierarchical model is proposed as a general mechanism of protein folding. In this model, protein folding occurs in a hierarchical manner, reflecting the hierarchy of the native three-dimensional structure, as embodied in the case of non-two-state folding with an accumulation of the molten globule state as a folding intermediate. The two-state folding is thus merely a simplified version of the hierarchical folding caused either by an alteration in the rate-limiting step of folding or by destabilization of the intermediate. -
Dynamics of Proteins in Solution Biophysics
Quarterly Reviews of Dynamics of proteins in solution Biophysics Marco Grimaldo1,2, Felix Roosen-Runge1,3, Fajun Zhang2, Frank Schreiber2 cambridge.org/qrb and Tilo Seydel1 1Institut Max von Laue - Paul Langevin, 71 avenue des Martyrs, 38042 Grenoble, France; 2Institut für Angewandte Physik, Universität Tübingen, Auf der Morgenstelle 10, 72076 Tübingen, Germany and 3Division for Physical Review Chemistry, Lund University, Naturvetarvägen 14, 22100 Lund, Sweden Cite this article: Grimaldo M, Roosen-Runge F, Abstract Zhang F, Schreiber F, Seydel T (2019). Dynamics of proteins in solution. Quarterly The dynamics of proteins in solution includes a variety of processes, such as backbone and Reviews of Biophysics 52, e7, 1–63. https:// side-chain fluctuations, interdomain motions, as well as global rotational and translational doi.org/10.1017/S0033583519000027 (i.e. center of mass) diffusion. Since protein dynamics is related to protein function and essen- tial transport processes, a detailed mechanistic understanding and monitoring of protein Received: 15 February 2019 Revised: 27 February 2019 dynamics in solution is highly desirable. The hierarchical character of protein dynamics Accepted: 4 March 2019 requires experimental tools addressing a broad range of time- and length scales. We discuss how different techniques contribute to a comprehensive picture of protein dynamics, and Key words: focus in particular on results from neutron spectroscopy. We outline the underlying principles Quasielastic neutron spectroscopy; protein diffusion; protein -
Conformational Search for the Protein Native State
CHAPTER 19 CONFORMATIONAL SEARCH FOR THE PROTEIN NATIVE STATE Amarda Shehu Assistant Professor Dept. of Comp. Sci. Al. Appnt. Dept. of Comp. Biol. and Bioinf. George Mason University 4400 University Blvd. MSN 4A5 Fairfax, Virginia, 22030, USA Abstract This chapter presents a survey of computational methods that obtain a struc- tural description of the protein native state. This description is important to understand a protein's biological function. The chapter presents the problem of characterizing the native state in conformational detail in terms of the chal- lenges that it raises in computation. Computing the conformations populated by a protein under native conditions is cast as a search problem. Methods such as Molecular Dynamics and Monte Carlo are treated rst. Multiscaling, the combination of reduced and high complexity models of conformations, is briey summarized as a powerful strategy to rapidly extract important fea- tures of the energy surface associated with the protein conformational space. Other strategies that narrow the search space through information obtained in the wet lab are also presented. The chapter then focuses on enhanced sam- Protein Structure Prediction:Method and Algorithms. By H. Rangwala & G. Karypis 1 Copyright c 2013 John Wiley & Sons, Inc. 2 CONFORMATIONAL SEARCH FOR THE PROTEIN NATIVE STATE pling strategies employed to compute native-like conformations when given only amino-acid sequence. Fragment-based assembly methods are analyzed for their success and what they are revealing about the physical process of folding. The chapter concludes with a discussion of future research directions in the computational quest for the protein native state. 19.1 THE QUEST FOR THE PROTEIN NATIVE STATE From the rst formulation of the protein folding problem by Wu in 1931 to the experiments of Mirsky and Pauling in 1936, chemical and physical properties of protein molecules were attributed to the amino-acid composition and structural arrangement of the protein chain [86, 56].