The aim of this thesis is to develop improved methods for calculating the free energy, entropy and enthalpy of solvation from molecular simulations.
Solvation thermodynamics of model compounds provides quantitative measurements used to analyze the stability of protein conformations in aqueous milieus. Solvation free energies govern the favorability of the solvation process, while entropy and enthalpy decompositions give insight into the molecular mechanisms by which the process occurs. Computationally, a coupling parameter λ modulates solute-solvent interactions to simulate an insertion process, and multiple lengthy simulations at a fixed λ value are typically required for free energy calculations to converge; entropy and enthalpy decompositions generally take 10-100 times longer.
This thesis presents three advances which accelerate the convergence of such calculations: (1) Development of entropy and enthalpy estimators which combine data from multiple simulations; (2) Optimization of λ schedules, or the set of parameter values associated with each simulation; (3) Validation of Hamiltonian replica exchange, a technique which swaps λ values between two otherwise independent simulations.
Taken together, these techniques promise to increase the accuracy and precision of free energy, entropy and enthalpy calculations. Improved estimates, in turn, can be used to investigate the validity and limits of existing solvation models and refine force field parameters, with the goal of understanding better the collapse transition and aggregation behavior of polypeptides.
|Advisor:||Pappu, Rohit V.|
|Commitee:||Baker, Nathan A., Carlsson, Anders E., Elbert, Donald L., Gelb, Lev D., Marshall, Garland R.|
|School:||Washington University in St. Louis|
|School Location:||United States -- Missouri|
|Source:||DAI-B 71/01, Dissertation Abstracts International|
|Subjects:||Condensed matter physics, Biophysics|
|Keywords:||Entropy decomposition, Free energy calculations, Free energy of solvation, Hamiltonian replica exchange, Molecular simulations, Solvation thermodynamics|
Copyright in each Dissertation and Thesis is retained by the author. All Rights Reserved
The supplemental file or files you are about to download were provided to ProQuest by the author as part of a
dissertation or thesis. The supplemental files are provided "AS IS" without warranty. ProQuest is not responsible for the
content, format or impact on the supplemental file(s) on our system. in some cases, the file type may be unknown or
may be a .exe file. We recommend caution as you open such files.
Copyright of the original materials contained in the supplemental file is retained by the author and your access to the
supplemental files is subject to the ProQuest Terms and Conditions of use.
Depending on the size of the file(s) you are downloading, the system may take some time to download them. Please be