Quantitative all-atom and coarse-grained molecular dynamics simulation studies of DNA

The remarkable molecule that encodes genetic information for all life on earth—DNA—is a polymer with unusual physical properties. The mechanical and electrostatic properties of DNA are utilized extensively by cells in the replication, regular maintenance, and expression of their genetic material. This can be illustrated by considering the journey of a typical gene regulating protein, the lac repressor, which recognizes a particular gene and prevents its expression. First, the large electrostatic charge density of DNA provides an energetic track that guides the repressor’s search for its target binding site. Next, as the protein moves along the DNA, it attempts to deform the DNA. The repressor is only able to form an active complex with DNA that has the right sequence-dependent flexibility. Finally, the repressor is believed to form a very small DNA loop that prevents the gene from being expressed. The stability of the loop can be expected to depend sensitively on the global flexibility of DNA. Thus, the key to understanding the some of the most important cellular processes lies in understanding the physical properties of DNA. Single-molecule experiments allow direct observation of the behavior of individual DNA molecules, but act on length and timescales that are often too large and fast to observe underlying DNA and DNA–protein dynamics. Acting on length and timescales that complement single-molecule experiments, molecular dynamics simulations provide a high-resolution glimpse into the mechanics of a biomolecular world. Here, several simulation studies are presented, each of which quantified one or more properties of DNA. Specifically, the repulsive forces between parallel duplex DNA molecules were measured; the short-ranged, attractive end-to-end stacking energy was obtained; a single-stranded DNA model was developed that reproduced experimental measurements of its extension upon applied force; and finally the nature of single-stranded DNA binding to a single-stranded DNA binding protein was investigated. These works represent important steps towards larger simulations of more biologically complete DNA–protein systems.

Name thesis:degree_name

Ph.D.

Level thesis:degree_level

Dissertation

Discipline thesis:degree_discipline

Physics

Grantor

University of Illinois at Urbana-Champaign

Year dc:date

2015

Author dc:creator

• Maffeo, Christopher

Contributors dc:contributor

• Aksimentiev, Aleksei
• Schulten, Klaus
• Ha, Taekjip
• Stack, John D.

• Deoxyribonucleic Acid (DNA)
• all-atom molecular dynamics
• coarse-grained molecular dynamics
• single-stranded DNA binding protein

Statement dc:rights

• Copyright 2014 Christopher Michael Maffeo

Language dc:language

en

Handle dc:identifier

http://hdl.handle.net/2142/72871

OAI identifier oai:identifier

oai:www.ideals.illinois.edu:2142/72871