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End-Point Free Energy Prediction using PB and MSSAS

Sun, Yuchen (2022) End-Point Free Energy Prediction using PB and MSSAS. Master's Thesis, University of Pittsburgh. (Unpublished)

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Solvation free energy (SFE) is a basic concept used in many areas. The accurate prediction of SFE lays the foundation for binding free energy prediction and it is also useful for the calculation of logarithm of 1-octanol-water partition coefficient (logP) which is a frequently used parameter in drug discovery. In this work, the performance of ABCG2 (AM1-BCC-GAFF2) charge model as well as other two charge models, i.e., RESP (Restrained Electrostatic Potential) and AM1-BCC (Austin Model 1-bond charge corrections) on SFE prediction of 633 small molecules in water by MM-PB/GBSA was evaluated. AM1-BCC charge model has the best performance of SFE prediction using GB1, PB_DELPHI methods with root mean square error (RMSE) of 1.88 kcal/mol, and 2.70 kcal/mol, respectively. Meanwhile, ABCG2 charge model performed better using GB2 and GB5 methods with RMSE of 2.06 kcal/mol and 2.17 kcal/mol, respectively. We further explored the influence of atom radii on the prediction accuracy and yielded a set of atom radii parameters suitable for more accurate SFE prediction using ABCG2 charge model by MM-PBSA method. Then, we tuned the nonpolar model for SFE calculation. Using our new model and parameters, for 544 training set molecules, the mean signed error (MSE) and RMSE of the SFE calculation decreased from -1.59 kcal/mol to 0 kcal/mol, and 2.38 kcal/mol to 1.05 kcal/mol, respectively. We then tested the new atom radii parameters on other charge models and found the new radii parameters also outperformed old ones in SFE prediction. Finally, the new radii parameters were adopted in the prediction of protein ligand binding free energy using MM-PBSA method. For the four systems tested, there is improved correlation between experiment and calculation results. And smaller error for absolute binding free energy were also observed, except for JNK1. We then applied the new radii parameters and adopted same approach to generate nonpolar SFE model for octanol SFE prediction. Based on that, a mix logP prediction model using physical method supported with empirical corrections was built. The superiority of our logP model was validated by smaller prediction error to drug-like molecules in ZINC database compared to other commonly used methods.


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Item Type: University of Pittsburgh ETD
Status: Unpublished
CreatorsEmailPitt UsernameORCID
Sun, Yuchenyus93@pitt.eduyus930000-0001-9936-0476
ETD Committee:
TitleMemberEmail AddressPitt UsernameORCID
Committee ChairFeng, Zhiweizhf11@pitt.eduzhf11
Committee CoChairKirisci,
Thesis AdvisorWang,
Committee MemberXie,
Date: 6 April 2022
Date Type: Publication
Defense Date: 25 March 2022
Approval Date: 6 April 2022
Submission Date: 3 April 2022
Access Restriction: No restriction; Release the ETD for access worldwide immediately.
Number of Pages: 76
Institution: University of Pittsburgh
Schools and Programs: School of Pharmacy > Pharmaceutical Sciences
Degree: MS - Master of Science
Thesis Type: Master's Thesis
Refereed: Yes
Uncontrolled Keywords: Free energy calculation, MM-PBSA
Date Deposited: 06 Apr 2022 16:29
Last Modified: 06 Apr 2022 16:29


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