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Advancing ab initio QM/MM Free Energy Calculations: Refining, Validating and
Quantifying the Reference Potential Approach
by
Nikolay V. Plotnikov
A Dissertation Presented to the
FACULTY OF THE USC GRADUATE SCHOOL
UNIVERSITY OF SOUTHERN CALIFORNIA
In Partial Fulfillment of the
Requirements for the Degree
DOCTOR OF PHILOSOPHY
(CHEMISTRY)
May 2013
Copyright 2013 Nikolay V. Plotnikov
Object Description
| Title | Advancing ab initio QM/MM free energy calculations: refining, validating and quantifying the reference potential approach |
| Author | Plotnikov, Nikolay V. |
| Author email | nplotnikov@gmail.com;plotniko@usc.edu |
| Degree | Doctor of Philosophy |
| Document type | Dissertation |
| Degree program | Chemistry |
| School | College of Letters, Arts And Sciences |
| Date defended/completed | 2013-03-21 |
| Date submitted | 2013-04-29 |
| Date approved | 2013-04-29 |
| Restricted until | 2013-04-29 |
| Date published | 2013-04-29 |
| Advisor (committee chair) | Warshel, Arieh |
| Advisor (committee member) |
Benderskii, Alexander V. Haworth, Ian |
| Abstract | Reliable computational modelling of chemical processes in condensed phases such as computation of the activation free energies requires both extensive configurational sampling and an appropriate level of theoretical treatment. The former is necessary for capturing solute-solvent fluctuations (which is extremely problematic in the energy-minimization approach) and for obtaining convergent free energies, while the latter is required for reliable description of redistribution of electron density during chemical processes and the corresponding energetics. These two factors make computational cost of ab initio QM/MM (QM(ai)/MM) simulations extremely high or even prohibitively expensive for the real system of interest such as chemical reactions in aqueous solution and enzymatic reactions. A powerful general approach, which circumvents these problems, is the reference potential based Paradynamics approach. In this approach the extensive configurational sampling is performed at a lower level of theory using a cheaper (computationally) reference potential rather than directly on the expensive target QM(ai)/MM potential. This is followed by calculating the free energy perturbation of moving from the reference potential to the target potential. ❧ In this work, a number of advances is presented which are made to the QM(ai)/MM free energy computation techniques in general and to the reference potential strategy in particular. First, a formulation of the reference potential based Paradynamics model is given. Chapter 1 addresses an important issue of improving the convergence of the linear response approximation (LRA), which is used to calculate the free energy perturbation from the EVB reference potential to the QM target potential. The improvement in the LRA convergence is achieved by iteratively reducing the difference between the two potentials by fitting EVB parameters to the energy and its derivatives of the target potential. A thorough comparative analysis of the computational cost of the Paradynamics approach is given relative to other methods based on the direct sampling of the target potential. In Chapter 2, an extensive study exploring, refining, and quantifying the Paradynamics model is given. First, a different refinement strategy for a general reference potential is formulated, where the difference between the reference potential and the target QM/MM surface is reduced using the correction potentials comprised of Gaussian functions along the reaction coordinates. Additionally we propose a way of accelerating the potential of mean force calculations by using a combination of the same correction potentials along the reaction coordinates and a solvent polarizing potential. Secondly, it is rigorously demonstrated how to gradually and in a controlled way improve calculations of the free energy perturbations associated with moving from the reference potential to the target QM/MM surface using the multi-step free energy perturbation approach. Furthermore, the LRA treatment is validate by comparing it to the full FEP approach. Finally, results of the PD model prediction for the activation barrier on the target potential are compared to results of PMF calculations. ❧ In chapter 3 we demonstrate practical applications of the QM(ai)/MM free energy calculation approach in general and the Paradynamics model in particular by addressing challenging questions in chemistry and related fields. Advances in developing computational tools for the free energy calculations required in the Paradynamics thermodynamic cycle are reported with illustrative examples. First, the Paradynamics model is applied to an enzymatic reaction, and its predictions are confirmed by 1D and 2D PMF calculations. Second, we calculate the catalytic effect of an enzyme. Last, we quantify another reference potential approach where the target free energy surface is estimated entirely by sampling the reference potential, and relating the corresponding probabilities. In chapter 4, a thorough computational study is carried out to quantify the mechanism of hydrolysis of a phosphate monoester, in particular the mechanism of proton transfer step. This is achieved by calculating the relevant QM(ai)/MM free energy surfaces for the possible mechanisms. This chapter also discusses application of the reference potential approach in estimating the nuclear quantum mechanical effect terms of the QCP approach. Finally, in the concluding Chapter 5 another application of the reference potential approach towards quantifying the photochemical cycle (which involves calculation of the excited state proton transfer) by calculating properties (the emission and absorption spectra) of the red fluorescent protein is considered. It is demonstrated how one can overcome the problem of prohibitively expensive QM(ai)/MM sampling for a system in the excited state by using the QCFF-PI reference potential. |
| Keyword | catalysis; free energy calculations; molecular dynamics; multi-scale modelling; quantum chemistry; reference potential |
| Language | English |
| Format (imt) | application/pdf |
| Part of collection | University of Southern California dissertations and theses |
| Publisher (of the original version) | University of Southern California |
| Place of publication (of the original version) | Los Angeles, California |
| Publisher (of the digital version) | University of Southern California. Libraries |
| Provenance | Electronically uploaded by the author |
| Type | texts |
| Legacy record ID | usctheses-m |
| Contributing entity | University of Southern California |
| Rights | Plotnikov, Nikolay V. |
| Physical access | The author retains rights to his/her dissertation, thesis or other graduate work according to U.S. copyright law. Electronic access is being provided by the USC Libraries in agreement with the author, as the original true and official version of the work, but does not grant the reader permission to use the work if the desired use is covered by copyright. It is the author, as rights holder, who must provide use permission if such use is covered by copyright. The original signature page accompanying the original submission of the work to the USC Libraries is retained by the USC Libraries and a copy of it may be obtained by authorized requesters contacting the repository e-mail address given. |
| Repository name | University of Southern California Digital Library |
| Repository address | USC Digital Library, University of Southern California, University Park Campus MC 7002, 106 University Village, Los Angeles, California 90089-7002, USA |
| Repository email | cisadmin@dots.usc.edu |
| Filename | etd-PlotnikovN-1629.pdf |
| Archival file | uscthesesreloadpub_Volume7/etd-PlotnikovN-1629.pdf |
Description
| Title | Page 1 |
| Contributing entity | University of Southern California |
| Repository email | cisadmin@dots.usc.edu |
| Full text | Advancing ab initio QM/MM Free Energy Calculations: Refining, Validating and Quantifying the Reference Potential Approach by Nikolay V. Plotnikov A Dissertation Presented to the FACULTY OF THE USC GRADUATE SCHOOL UNIVERSITY OF SOUTHERN CALIFORNIA In Partial Fulfillment of the Requirements for the Degree DOCTOR OF PHILOSOPHY (CHEMISTRY) May 2013 Copyright 2013 Nikolay V. Plotnikov |
