Document Type

Dissertation

Date of Degree

Fall 2014

Degree Name

PhD (Doctor of Philosophy)

Degree In

Biochemistry

First Advisor

Adrian H. Elcock

Second Advisor

Marc S. Wold

Abstract

The use of computational simulation to study the dynamics and interactions of macromolecules has become an important tool in the field of biochemistry. A common method to perform these simulations is to use all-atom explicit-solvent molecular dynamics (MD). However, due to the limitations in computational power currently available, this method is not practical for simulating large-scale biomolecular systems on long timescales. An alternative is to perform implicit-solvent Brownian dynamics (BD) simulations using a coarse grained (CG) model that allows for increased computational efficiency. However, if simulations using the CG model are not realistic, then the gain in computational efficiency from using a CG model is not worthwhile.

This thesis describes the derivation of a set of bonded and nonbonded CG potential functions for use in implicit-solvent BD simulations of proteins derived from all-atom explicit-solvent MD simulations of amino acids. To determine which force field and water model to use in the MD simulations, Chapter II describes 1 Μs all-atom explicit-solvent MD simulations of glycine, asparagine, phenylalanine, and valine solutions at 50, 100, 200 and 300 mg/ml concentrations performed using eight different force field and water model combinations. To evaluate the accuracy of the force fields at high solute concentrations, the density, viscosity, and dielectric increments of the four amino acids were calculated from the simulations and compared to experimental results. Additionally, the change in the strength of hydrophobic and electrostatic interactions with increasing solute concentration was calculated for each force field and water model combination. As a result of this study, the Amber ff99SB-ILDN force field and TIP4P-Ew explicit-solvent water model were chosen for all subsequent MD simulations. Chapter III describes the derivation of CG bonded potential functions from 1 Μs all-atom explicit-solvent MD simulations of each of the twenty amino acids, including a separate simulation for protonated histidine. The angle and dihedral probability distributions sampled during the MD simulations were used to optimize the bonded potential functions using the iterative Boltzmann inversion (IBI) method. Chapter IV describes the derivation of CG nonbonded potential functions from 1 Μs all-atom explicit-solvent MD simulations of every possible pairing of the amino acids (231 different systems). The radial distribution functions calculated from these MD simulations were used to optimize a set of nonbonded CG potential functions using the IBI method. The optimized set of bonded and nonbonded potential functions, which is termed COFFDROP (COarse-grained Force Field for Dynamic Representation Of Proteins), quantitatively reproduced all of the calculated MD distributions. To determine if COFFDROP would be useful for simulations of bimolecular systems, Chapter V describes the testing of the transferability of the force field. First, COFFDROP was used to simulate concentrated amino acid solutions. The clustering of the solutes in these simulations was directly compared with results from corresponding all-atom explicit-solvent MD simulations and found to be in excellent agreement. Next, BD simulations of 9.2 mM solutions of the small protein villin headpiece were performed. The proteins aggregated during these simulations, which is in agreement with results from MD simulation but in disagreement with experiment. After scaling the strength of COFFDROP's nonbonded potential functions by a factor of 0.8 and rerunning the BD simulations, the amount of aggregation was comparable to experimental observations. Based on these results, COFFDROP is likely to be applicable in CG BD simulations of large, highly concentrated, biomolecular systems.

Public Abstract

In the past four decades, computational simulation has proven to be a very useful technique to investigate questions relating to proteins and other biological macromolecules. These simulations have allowed scientists to better understand the dynamics of individual proteins, and the interactions of multiple proteins on the atomic level. However, due to the current limitations in computational power, it is difficult to simulate large biological systems on the atomic level for long enough to gain insights into biochemical processes. One solution to this problem is not to explicitly represent every atom in a protein during a simulation, but rather group together many atoms and represent them as a single sphere or “pseudoatom”. This process is known as coarse graining. It is important, however, that simulations performed using coarse grained models generate data that are consistent with simulations performed using atomic level resolution models and experimental results. This thesis describes a coarse grain model for proteins that has been parameterized to replicate the behavior of more detailed atomic level simulations. To determine how accurate the model is, its predictions were compared to experimental measurements. Following the testing of the model, it should be possible to use it in simulations of large biological systems to answer questions relevant to the field of biochemistry.

Keywords

publicabstract, Brownian Dynamics, Coarse Grain, Force Field, Molecular Dynamics

Pages

xv, 189 pages

Bibliography

Includes bibliographical references (pages 172-189).

Copyright

Copyright 2014 Casey Tyler Andrews

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Biochemistry Commons

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