Multiscale Modeling of Biomolecular Complexes

Macromolecular complexes carry out cellular processes that span many different length and time scales. Central to their function are both large-scale conformational changes, and atomic-atomic scale events. Molecular dynamics (MD) simulations are well suited to study the structural dynamics of such complexes in atomic detail. However, large complexes undergoing conformational changes or systems where atomic structures of all components are not available call for the combination of different levels of resolution into so-called multiscale simulations. This thesis presents two multiscale methodologies. The first is a novel method to model complexes between protein and DNA that contain looped or coiled DNA. The approach combines a coarse-grained model of the DNA loop, based on the classical theory of elasticity, with an atomic model of proteins and protein-DNA interfaces based on molecular dynamics. The method is applied to the E. coli lac repressor, a landmark protein of genetic regulation, that forces DNA into a loop to prevent transcription. The structural dynamics of the complex are revealed by the multiscale simulations, suggesting the mechanisms by which the protein absorbs the strain from DNA, and the structure of the DNA loop it induces. The second method was developed to flexibly fit atomic structures into electron microscopy (EM) maps using molecular dynamics simulations. The simulations incorporate the EM data as an external potential added to the molecular dynamics force field, allowing all internal features present in the EM map to be used in the fitting process, while the model remains fully flexible and stereochemically correct. Validation for the molecular dynamics flexible fitting (MDFF) method using available crystal structures of protein and RNA in different conformations are introduced, as well as measures to assess and monitor the fitting process. The MDFF method is used to obtain high-resolution structures of the E. coli ribosome in different functional states imaged by cryo-EM. Overall, this thesis illustrates the need to develop methods that combine different resolutions tailored to the study of macromolecular processes that furnish atomic detail when needed.

Name thesis:degree_name

Ph.D.

Level thesis:degree_level

Dissertation

Discipline thesis:degree_discipline

Biophysics and Computational Biology

Grantor

University of Illinois at Urbana-Champaign

Year dc:date

2014

Author dc:creator

• Villa Rodriguez, Elizabeth

Contributors dc:contributor

• Schulten, Klaus J.

• Biophysics, General

Identifier

(UMI)AAI3314926

OAI identifier oai:identifier

oai:www.ideals.illinois.edu:2142/72397