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Neumann, Jan (2011): Molecular dynamics simulations of protein-protein interactions and THz driving of molecular rotors on gold. Dissertation, LMU München: Faculty of Physics
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Abstract

The scope of this work is to gain insight and a deeper understanding of exploring and controlling molecular devices like proteins and rotors by fine tuned manipulation via mechanical or electrical energies. I focus on three main topics. First, I investigate vectorial forces as a tool to explore the energy landscape of protein complexes. Second, I apply this method to a biologically important force transduction complex, the integrin-talin complex. Third, I use Terahertz electric fields to manipulate the energy landscape of a molecular rotor on a gold surface and drive their effective rotation bidirectionally. Force is by nature a vector and depends on its three parameters: magnitude, direction and attachment point. Here, the impact of different force protocols varying these parameters is shown for an antibody-antigen complex and the ribonuclease-inhibitor complex barnase-barstar. Antibodies are essential for our adaptive immune system in their function to bind specific antigens. Here, the binding of an antibody to a peptide is probed with varying attachment points. Different attachment points clearly change the dissociation pathways. The barriers identified using experimental atomic force microscopy (AFM) and molecular dynamics (MD) simulations are in excellent agreement. I determine the molecular interactions of two main barriers for each setup. This results in a common outer barrier of the complex and different inner barriers probed by AFM. The ribonuclease barnase and its inhibitor barstar form an evolutionary optimized complex. Different force protocols are shown to determine the hierarchy of relative stability within a protein complex. For the barnase-barstar complex, the internal fold of the barstar is identified to be less stable than the barnase-barstar binding interaction. High velocities probe the lability or barriers of the system while low velocities probe the stability or energy wells of this system. Forces impact biological life on totally different length scales which range from whole organisms to individual proteins. Integrins are the major cell adhesion receptors binding to the extracellular matrix and talin. Talin activates the integrins and creates the initial connection to the actin cytoskeleton of the cell. Here, I have chosen to investigate the integrin-talin complex as a biologically important force transduction complex. The force dependence of the system is probed by constant force MD simulations. The two main results include the activation of the complex and its force response. I demonstrate, that the binding of talin to integrin does not disrupt the integrin's transmembrane helix interactions sterically. Since, this disruption is necessary for integrin activation, a modified activation mechanism requiring a small force application is proposed. The response of the integrin-talin complex normal and parallel to the cell membrane is analyzed. The complete dissociation pathways generated for both directions identify a force-induced formation of a stabilizing beta strand between integrin and talin only for normal forces. Furthermore, the complex tries to rotate such that the external force aligns with the more force resistant axis of the complex. In nature, molecular rotors are essential building blocks of many molecular machines and brownian motors like the F1-ATPase or the flagellum of a bacterium. The direction of rotation often steers different processes in clockwise and counterclockwise directions. Rotation on the nanoscopic level in artificial devices is still very limited and requires a deeper understanding. In my last project, I study the switching and driving of a molecular diethylsulfid rotor on a gold (111) surface by Terahertz electric fields. The response of the rotational energy landscape to static and oscillation electric fields is analyzed. Varying the Terahertz driving frequency, the rotation direction and frequency are controlled. A theoretical framework is presented to describe the behavior of the molecular rotor. This can be seen as the first step into the direction of man-made controllable nano-devices driven and controlled by energy from the electric wall-socket.

Abstract

Proteine sind die molekularen Maschinen der Zelle. Sie gehören zu den essentiellen Grundbausteinen des Lebens und dynamische Protein-Protein Wechselwirkungen steuern das Leben auf zellulärer Ebene. Thema dieser Arbeit ist es mittels Computersimulationen ein besseres Verständnis von Proteinkomplexen und molekularen Rotoren zu erlangen. Hierbei konzentriere ich mich auf drei Schwerpunktthemen: Erstens trage ich dazu bei ein besseres Verständnis zur methodischen Untersuchung der Energielandschaften von Proteinen und Proteinkomplexen mittels der Anwendung vektorieller Kräfte zu erlangen. Am Beispiel eines Antikörper-Antigen und eines Ribonuclease-Inhibitor Komplexes werden die Auswirkungen verschiedener Kraftparameter (Betrag, Richtung, Angriffspunkt und Zuggeschwindigkeit) auf die Entwicklung des Systems unter Krafteinfluss untersucht. Hervorzuheben sind die exzellenten Übereinstimmungen zwischen experimentellen Ergebnissen der Atomaren Kraftmikroskopie mit den Molekular Dynamik Simulationen im Antikörper-Projekt. Zweitens studiere ich den Integrin-Talin Komplex, welcher die initiale kraftleitende Verbindung zwischen Zellinnerem und -äußerem schafft. Die zwei wichtigsten Ergebnisse sind die Erweiterung des Aktivierungsmechanismusses des Integrins um eine zusätzlich benötigte Kraftkomponente und die Entdeckung der kraftinduzierten Stabilisierung des Komplexes durch die Ausbildung eines stabilisierenden beta-Faltblatts zwischen Integrin und Talin. In meinem dritten Projekt untersuche ich einen diethylsulfid Rotor auf einer Gold (111) Oberfläche mittels MD Simulationen. Die Energielandschaft dieses Rotors kann mit elektrischen Feldern im Terahertzbereich so manipuliert werden, dass die effektive Rotationsrichtung und -frequenzen im Gigahertzbereich gesteuert werden kann. Eine theoretische Beschreibung dieses Phänomens und seine Abhängigkeit von der Struktur des Rotors werden behandelt. Dies kann ein erster Schritt zu einem Interface zwischen bekannten elektrischen Schaltungen und zukünftigen artifiziellen Nanomaschinen sein.