TY - BOOK

T1 - Protein dynamics from integrated experiment and simulation

AU - Bengtsen, Tone

PY - 2019

Y1 - 2019

N2 - This thesis aims to describe the dynamics of proteins. Protein dynamics concerns the structural changes of proteins and are important in enabling molecular interactions, signal forwarding, enzyme catalysis etc. The research performed are based on molecular dynamics, a computational simulation method particular useful for investigating protein dynamics. As protein dynamics are difficult to fully capture by any single method, the work integrates experimental methods withcomputational simulations to obtain a richer understanding of protein dynamics. This thesis describes three research projects that concerns protein dynamics and the integration of molecular simulations with biophysical experiments. The first project gives a thorough practical introduction to the field of integration by reweighting. Using a flexible two domain protein as a showcase, it illustrates how integration with experimental SAXS improves the description of the dynamical domain-domain motions, and demonstrates how integration can facilitate the use of more efficient but less accurate force fields. The second project describes the results of extensive research performed on the nanodisc, an important membrane mimetic in biophysical studies. The project is performed in cooperation with the groupof Lise Arleth. The combination of both SAXS, SANS, differential scanning calorimetry and simulations increases the understanding of both structure and dynamics and describes elliptical fluctuations in the conformations. In addition, integration of simulations with experimental data are used to bridge apparent structural deviations between the solution based methods, SAXS and NMR. The third project investigates the opening and closing dynamics of the membrane protein CorA, a bacterial magnesium transporter. The work is performed in tight cooperation with the group of Lise Arleth and employs a multitude of methods. The results of SANS experiments suggest that the structure and dynamics of CorA are similar in both the open, magnesium transporting state, and in the closed state. Simulations are used to investigate the structural and dynamics basis for the observed SAXS. Integration of simulations with SANS shows global dynamics and underlying asymmetrical conformations suggesting the need to reevaluated previous proposed models for the opening and closing dynamics.

AB - This thesis aims to describe the dynamics of proteins. Protein dynamics concerns the structural changes of proteins and are important in enabling molecular interactions, signal forwarding, enzyme catalysis etc. The research performed are based on molecular dynamics, a computational simulation method particular useful for investigating protein dynamics. As protein dynamics are difficult to fully capture by any single method, the work integrates experimental methods withcomputational simulations to obtain a richer understanding of protein dynamics. This thesis describes three research projects that concerns protein dynamics and the integration of molecular simulations with biophysical experiments. The first project gives a thorough practical introduction to the field of integration by reweighting. Using a flexible two domain protein as a showcase, it illustrates how integration with experimental SAXS improves the description of the dynamical domain-domain motions, and demonstrates how integration can facilitate the use of more efficient but less accurate force fields. The second project describes the results of extensive research performed on the nanodisc, an important membrane mimetic in biophysical studies. The project is performed in cooperation with the groupof Lise Arleth. The combination of both SAXS, SANS, differential scanning calorimetry and simulations increases the understanding of both structure and dynamics and describes elliptical fluctuations in the conformations. In addition, integration of simulations with experimental data are used to bridge apparent structural deviations between the solution based methods, SAXS and NMR. The third project investigates the opening and closing dynamics of the membrane protein CorA, a bacterial magnesium transporter. The work is performed in tight cooperation with the group of Lise Arleth and employs a multitude of methods. The results of SANS experiments suggest that the structure and dynamics of CorA are similar in both the open, magnesium transporting state, and in the closed state. Simulations are used to investigate the structural and dynamics basis for the observed SAXS. Integration of simulations with SANS shows global dynamics and underlying asymmetrical conformations suggesting the need to reevaluated previous proposed models for the opening and closing dynamics.

M3 - Ph.D. thesis

BT - Protein dynamics from integrated experiment and simulation

PB - Department of Biology, Faculty of Science, University of Copenhagen

ER -