Methods for increasing model accuracy and simulation time scales of biological processes with molecular dynamics

This dissertation presents three research projects on novel methods in computational bio- physics. Each of these projects introduces methodologies to extend the capabilities of molecular dynamics simulations in one way or another. In the first chapter, molecular dynamics simulations and the central role they play in the field of structural biology is introduced to give the reader some background on the common basis of the projects. The second chapter describes the first of these projects, where the molecular dynamics flexible fitting method for refining molecular structures of macromolecules using experimental electron density data is extended to be able to handle high-resolution density data, which are becoming increasingly commonplace. The third chapter focuses on adaptive multilevel splitting, a replica-based sampling technique that was employed in molecular dynamics simulations to measure the rate of drug molecule dissociation, a process that occurs on the order of milliseconds and above, which is out of the reach of typical molecular dynamics simulations. In the final chapter, a kinetic model of diffusion is introduced. This model allows simulation of the diffusion of small molecules in arbitrary potentials, for example, those that characterize the space around and within a membrane protein channel. The adaptive discretization scheme allows simulations between the micro- to millisecond time scales, which are typical of diffusive processes. This collection of projects is a snapshot of the diversity and versatility of current problems in structural biology that can be addressed by molecular dynamics simulations. I hope to instill in the reader a sense of how method development in molecular dynamics will expand the contributions of the field to both scientific and practical pursuits in biology.

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

2017

Author dc:creator

• Teo, Koon Heng Ivan

Contributors dc:contributor

• Schulten, Klaus
• Aksimentiev, Oleksii
• Tajkhorshid, Emad
• Chemla, Yann Robert
• Hübler, Alfred Wilhelm

• molecular dynamics
• cryo-electron microscopy
• flexible fitting
• adaptive multilevel splitting
• rare event
• kinetic model
• benzamidine
• trypsin
• diffusion
• Smoluchowski equation
• self-organizing map
• structure refinement

Statement dc:rights

• Copyright 2016 Koon Heng Ivan Teo

Language dc:language

en

Handle dc:identifier

http://hdl.handle.net/2142/95286

OAI identifier oai:identifier

oai:www.ideals.illinois.edu:2142/95286