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Polymer and Protein Physics: Simulations of Interactions and Dynamics
Uppsala University, Disciplinary Domain of Science and Technology, Physics, Department of Physics and Astronomy, Materials Theory.
2021 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Proteins can, without any exaggeration, be called the "building blocks of life". Their physical properties depend not only on the chemical structure but also on their geometric shape. In this thesis, I investigate protein geometry using several different methods.

We start with a coarse-graining model to study the general behavior of polymers. For this reason, we utilize an effective Hamiltonian that can describe the thermodynamic properties of polymer chains and reproduce secondary and tertiary structures. To investigate this model, I perform classical Monte Carlo simulations using my software package.

Another problem we address in this thesis is how to distinguish thermodynamic phases of proteins. The conventional definition of phases of polymer systems uses scaling laws. However, this method needs the chain's length to be varied, which is impossible to do with heteropolymers where the number of sites is one of the system's characteristics. We will apply renormalization group (RG) theory ideas to overcome this difficulty. We present a scaling procedure and an observable through which RG flow can define a certain polymer chain's phase.

Another part of the thesis is dedicated to the method of molecular dynamics. Our focus is on a novel experimental technique called Single Particle Imaging (SPI). The spatial orientation of the sample in this method is arbitrary. Scientists proposed to use a strong electric field to fix the orientation since most biological molecules have a non-zero dipole moment. Motivated by this, we investigate the influence of a strong electric field's ramping on the orientation of protein ubiquitin. For the same question of SPI and using the same protein, we study the reproducibility of unfolding it in a strong electric field. With the help of a new graph representation, I show different unfolding pathways as a function of the electric field's value and compare them with thermal and mechanical unfolding. I show that the RG flow observable can also detect the different ubiquitin unfolding pathways more simply.

The study described in this thesis has two types of results. One is a very concrete type, which can be utilized right away in the SPI experiments, like MS SPIDOC on the European XFEL. The other type of results are more theoretical and opens up a new field for further research. However, all of them contribute to protein science, an area vital for humanity's ability to protect us from threats such as the current COVID-19 pandemic.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2021. , p. 126
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Science and Technology, ISSN 1651-6214 ; 2015
Keywords [en]
polymers, proteins, Monte Carlo, molecular dynamics, phase diagram, renormalisation group, SPI, polymer effective model, coarse-graining
National Category
Biophysics
Research subject
Physics with specialization in Biophysics
Identifiers
URN: urn:nbn:se:uu:diva-434275ISBN: 978-91-513-1139-5 (print)OAI: oai:DiVA.org:uu-434275DiVA, id: diva2:1526388
Public defence
2021-03-26, Polhemsalen, Ångströmlaboratoriet, Lägerhyddsvägen 1, Uppsala, 13:30 (English)
Opponent
Supervisors
Available from: 2021-03-04 Created: 2021-02-08 Last updated: 2021-03-29
List of papers
1. Phase diagram and the pseudogap state in a linear chiral homopolymer model
Open this publication in new window or tab >>Phase diagram and the pseudogap state in a linear chiral homopolymer model
2015 (English)In: Physical Review E. Statistical, Nonlinear, and Soft Matter Physics, ISSN 1539-3755, E-ISSN 1550-2376, Vol. 92, no 3, article id 032602Article in journal (Refereed) Published
Abstract [en]

The phase structure of a single self-interacting homopolymer chain is investigated in terms of a universal theoretical model, designed to describe the chain in the infrared limit of slow spatial variations. The effects of chirality are studied and compared with the influence of a short-range attractive interaction between monomers, at various ambient temperature values. In the high-temperature limit the homopolymer chain is in the self-avoiding random walk phase. At very low temperatures two different phases are possible: When short-range attractive interactions dominate over chirality, the chain collapses into a space-filling conformation. But when the attractive interactions weaken, there is a low-temperature unfolding transition and the chain becomes like a straight rod. Between the high- and low-temperature limits, several intermediate states are observed, including the theta regime and pseudogap state, which is a novel form of phase state in the context of polymer chains. Applications to polymers and proteins, in particular collagen, are suggested.

National Category
Physical Sciences
Identifiers
urn:nbn:se:uu:diva-264627 (URN)10.1103/PhysRevE.92.032602 (DOI)000361310700003 ()
Funder
Swedish Research CouncilCarl Tryggers foundation
Available from: 2015-10-26 Created: 2015-10-15 Last updated: 2021-02-08Bibliographically approved
2. Multiple scales and phases in discrete chains with application to folded proteins
Open this publication in new window or tab >>Multiple scales and phases in discrete chains with application to folded proteins
2018 (English)In: Physical review. E, ISSN 2470-0045, E-ISSN 2470-0053, Vol. 97, no 5, article id 052107Article in journal (Refereed) Published
Abstract [en]

Chiral heteropolymers such as large globular proteins can simultaneously support multiple length scales. The interplay between the different scales brings about conformational diversity, determines the phase properties of the polymer chain, and governs the structure of the energy landscape. Most importantly, multiple scales produce complex dynamics that enable proteins to sustain live matter. However, at the moment there is incomplete understanding of how to identify and distinguish the various scales that determine the structure and dynamics of a complex protein. Here we address this impending problem. We develop a methodology with the potential to systematically identify different length scales, in the general case of a linear polymer chain. For this we introduce and analyze the properties of an order parameter that can both reveal the presence of different length scales and can also probe the phase structure. We first develop our concepts in the case of chiral homopolymers. We introduce a variant of Kadanoff's block-spin transformation to coarse grain piecewise linear chains, such as the C alpha backbone of a protein. We derive analytically, and then verify numerically, a number of properties that the order parameter can display, in the case of a chiral polymer chain. In particular, we propose that in the case of a chiral heteropolymer the order parameter can reveal traits of several different phases, contingent on the length scale at which it is scrutinized. We confirm that this is the case with crystallographic protein structures in the Protein Data Bank. Thus our results suggest relations between the scales, the phases, and the complexity of folding pathways.

Place, publisher, year, edition, pages
American Physical Society, 2018
National Category
Physical Chemistry
Identifiers
urn:nbn:se:uu:diva-357014 (URN)10.1103/PhysRevE.97.052107 (DOI)000432978200001 ()
Funder
Knut and Alice Wallenberg FoundationSwedish Research Council
Available from: 2018-08-13 Created: 2018-08-13 Last updated: 2021-02-08Bibliographically approved
3. RG Smoothing Algorithm Which Makes Data Compression
Open this publication in new window or tab >>RG Smoothing Algorithm Which Makes Data Compression
2018 (English)In: arXiv preprint arXiv:1806.01663Article in journal (Other academic) Published
Abstract [en]

I describe a new method for smoothing a one-dimensional curve in Euclidian space with an arbitrary number of dimensions. The basic idea is borrowed from renormalization group theory which previously was applied to biological macromolecules. There are two crucial differences from other smoothing methods that make the algorithm unique: data compression and recursive implementation. One of the simplest forms of the method that is described in this article has only one free parameter - the number of iterative steps. This means that hardware implementation should be relatively easy because each loop is simple and strictly defined. The method could be beneficially applied to pattern recognition and data compression in future studies.

National Category
Computer Sciences
Identifiers
urn:nbn:se:uu:diva-434242 (URN)
Available from: 2021-02-06 Created: 2021-02-06 Last updated: 2021-11-10Bibliographically approved
4. Reproducibility in the unfolding process of protein induced by an external electric field
Open this publication in new window or tab >>Reproducibility in the unfolding process of protein induced by an external electric field
Show others...
2021 (English)In: Chemical Science, ISSN 2041-6520, E-ISSN 2041-6539, Vol. 12, no 6, p. 2030-2038Article in journal (Refereed) Published
Abstract [en]

The dynamics of proteins are crucial for their function. However, commonly used techniques for studying protein structures are limited in monitoring time-resolved dynamics at high resolution. Combining electric fields with existing techniques to study gas phase proteins, such as Single Particle Imaging using Free-electron Lasers and gas phase Small Angle X-ray Scattering, has the potential to open up a new era in time-resolved studies of gas phase protein dynamics. Using molecular dynamics simulations, we identify well-defined unfolding pathways of a protein, induced by experimentally achievable external electric fields. Our simulations show that strong electric fields in conjunction with short pulsed X-ray sources such as Free-electron Lasers can be a new path for imaging dynamics of gas-phase proteins at high spatial and temporal resolution.

Place, publisher, year, edition, pages
Royal Society of ChemistryRoyal Society of Chemistry (RSC), 2021
National Category
Biophysics Physical Chemistry
Identifiers
urn:nbn:se:uu:diva-429912 (URN)10.1039/D0SC06008A (DOI)000619216100039 ()
Funder
EU, Horizon 2020, 801406Swedish Research Council, 2018-00740
Available from: 2021-01-06 Created: 2021-01-06 Last updated: 2024-01-15Bibliographically approved
5. Orientation before destruction. A multiscale molecular dynamics study
Open this publication in new window or tab >>Orientation before destruction. A multiscale molecular dynamics study
Show others...
(English)Manuscript (preprint) (Other academic)
Abstract [en]

The emergence of ultra-fast X-ray free-electron lasers opens the possibility of imaging single molecules in the gas phase at atomic resolution. The main disadvantage of this imaging technique is the unknown orientation of the sample exposed to the X-ray beam, making the three-dimensional reconstruction not trivial. The induced orientation of molecules prior to X-ray exposure can be highly beneficial, as it significantly reduces the number of collected diffraction patterns whilst improving the quality of the reconstructed structure. We present here the possibility of protein orientation using a time-dependent external electric field. We used ab initio simulations on Trp-cage protein to provide a qualitative estimation of the field strength required to break protein bonds, with 45 V/nm as a breaking point value. Furthermore, we simulated, in a classical molecular dynamics approach, the orientation of ubiquitin protein by exposing it to different time-dependent electric fields. The protein structure was preserved for all samples at the moment orientation was achieved, which we denote `orientation before destruction'. Moreover, we find that the minimal field strength required to induce orientation within ten ns of electric field exposure was of the order of 0.5 V/nm. Our results help explain the process of field orientation of proteins and can support the design of instruments for protein orientation.

National Category
Biophysics
Identifiers
urn:nbn:se:uu:diva-434280 (URN)
Available from: 2021-02-08 Created: 2021-02-08 Last updated: 2021-02-08
6. NMR Refinement and Peptide Folding Using the GROMACS Software
Open this publication in new window or tab >>NMR Refinement and Peptide Folding Using the GROMACS Software
2021 (English)In: Journal of Biomolecular NMR, ISSN 0925-2738, E-ISSN 1573-5001, Vol. 75, no 4-5, p. 143-149Article in journal (Refereed) Published
Abstract [en]

Nuclear magnetic resonance spectroscopy is used routinely for studying the three-dimensional structures and dynamics of proteins. Structure determination is usually done by adding restraints based upon NMR data to a classical energy function and performing restrained molecular simulations. Here we report on the implementation of a script to extract NMR restraints from a NMR-STAR file and export it to the GROMACS software. With this package, it is possible to model distance restraints, dihedral restraints, and orientation restraints. The output from the script is validated by performing simulations with and without restraints, including the ab initio refinement of one peptide.

Place, publisher, year, edition, pages
Springer NatureSpringer Nature, 2021
Keywords
Python, NMR-STAR, Force Field, Amber, Charmm
National Category
Biophysics Physical Chemistry
Identifiers
urn:nbn:se:uu:diva-434243 (URN)10.1007/s10858-021-00363-z (DOI)000634305400001 ()33778935 (PubMedID)
Available from: 2021-02-06 Created: 2021-02-06 Last updated: 2024-01-15Bibliographically approved

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