Protein flexibility and conformational ensembles from kino-geometric modeling and sampling to motion planning

Eigenmittelfinanziertes Projekt


Details zum Projekt

Projektleiter/in:
Prof. Dr.-Ing. Sigrid Leyendecker

Projektbeteiligte:
Dominik Budday

Beteiligte FAU-Organisationseinheiten:
Lehrstuhl für Technische Dynamik

Projektstart: 01.06.2014
Projektende: 31.03.2019


Forschungsbereiche

biomechanics
Lehrstuhl für Technische Dynamik
multibody dynamics and robotics
Lehrstuhl für Technische Dynamik


Abstract (fachliche Beschreibung):

Proteins are dynamic macromolecules that perform their biological functions by exchanging between different conformational substates on a broad range of spatial and temporal scales. As the underlying energy landscapes that govern these conformational changes are very rough and often contain high energy barriers, efficient, yet atomically detailed simulations to understand and predict biophysically relevant motions remain challenging.

This project aims at providing functional insights into protein molecular mechanisms from simplified kinematic and geometric modeling. Guided by the covalent bond structure of the molecule, we construct kinematic multi-body systems with dihedral degrees of freedom and non-covalent interactions as constraints, which allows us to efficiently analyze conformational flexibility and deform the protein while maintaining secondary structure. Our analyses show convincing agreement with experimental data from various resources and more detailed Molecular Dynamics simulations, demonstrating the power of kino-geometric models for fast insights into protein flexibility and functional mechanisms, with broad implications for drug design and human health.


Publikationen
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Budday, D. (2019). High-Dimensional Robotics at the Nanoscale — Kino-Geometric Modeling of Proteins and Molecular Mechanisms (Dissertation).
Budday, D., Leyendecker, S., & van den Bedem, H. (2018). Bridging protein rigidity theory and normal modes using kino-geometric analysis. In Proceedings of the GAMM Annual Meeting. München, DE.
Fonseca, R., Budday, D., & van den Bedem, H. (2018). Collision-free poisson motion planning in ultra high-dimensional molecular conformation spaces. Journal of Computational Chemistry. https://dx.doi.org/10.1002/jcc.25138
Budday, D., Leyendecker, S., & van den Bedem, H. (2018). Kinematic Flexibility Analysis: Hydrogen Bonding Patterns Impart a Spatial Hierarchy of Protein Motion. Journal of Chemical Information and Modeling, 58(10), 2108-2122. https://dx.doi.org/10.1021/acs.jcim.8b00267
Héliou, A., Budday, D., Fonseca, R., & van den Bedem, H. (2017). Fast, clash-free RNA conformational morphing using molecular junctions. Bioinformatics. https://dx.doi.org/10.1093/bioinformatics/btx127
Budday, D., Fonseca, R., Leyendecker, S., & van den Bedem, H. (2017). Frustration-guided motion planning reveals conformational transitions in proteins. Proteins-Structure Function and Bioinformatics, 85(10), 1795-1807. https://dx.doi.org/10.1002/prot.25333
Budday, D., Fonseca, R., Leyendecker, S., & van den Bedem, H. (2016). Clash- and constraint guided motion planning reveals conformational transition pathways in proteins. Poster presentation, Santa Monica, California, US.
Budday, D., Fonseca, R., Leyendecker, S., & van den Bedem, H. (2016). Frustration-guided motion planning reveals conformational transitions in proteins. Durham, North Carolina, US.
Budday, D., Fonseca, R., Leyendecker, S., & van den Bedem, H. (2016). Frustration-guided motion planning reveals conformational transitions in proteins. In Proceedings of the 3DSIG. Orlando, Florida, US.
Budday, D., Fonseca, R., Héliou, A., Leyendecker, S., & van den Bedem, H. (2016). Navigating protein conformation spaces by kino-geometric sampling and modulating frustrated motions. Poster presentation at Annual Meeting of the German Biophysical Society, Erlangen, DE.

Zuletzt aktualisiert 2019-26-08 um 17:36