The long-term objective of this proposal is to produce and apply methods and tools for chemically accurate and computationally efficient molecular simulations. The targets of the simulations are organic, physical, and biological systems (including proteins and peptides). The results of this work will be available to the general scientific community. The emphasis of the methodological part of this proposal will be on accurate and computationally inexpensive inclusion of electrostatic polarization. The following specific goals will be set with the above long-term objective in mind: A software suit will be developed for molecular modeling with a fast polarization technique employed. The technique has been previously proposed and tested by the author. Its application resulted in obtaining accurate results with a ca. an order of magnitude increase in computational speed. Force field parameters to be used with the model will be produced for a variety of biologically significant organic and protein molecules. The author has an extensive amount of experience with such tasks, including development of polarizable and non-polarizable protein force fields. In the proposed research, the main source of the target fitting data will be high-level quantum mechanical calculations. Two major directions of applications are planned. First, accurate predictions of protein pKa values will be conducted. Accurate assessment of pKa values of protein residues is important in predicting protein stability, solubility, and biological activity. The first two major targets in this project will be the turkey ovomuvoid third domain and ribonuclease Sa. Second, the fast polarization technique, combined with the Monte Carlo method, will be applied to studies of effective farnesyl transferase inhibitors. While farnesyl transferase has been acknowledged as a very valid target for anti-cancer inhibition, synthetic reproduction of some of the most potent natural inhibitors (such as the CP-type) is often very challenging due to the structure of the inhibitors. The author hopes that the accuracy of the polarizable force field, combined with the speed of the employed implementation and the true thermodynamic sampling in the Monte Carlo form will allow to assess binding energy tendencies adequately enough to suggest easier-to synthesize potent inhibitors - analogues of the natural products and peptidomimetics.

National Institute of Health (NIH)
National Institute of General Medical Sciences (NIGMS)
Research Project (R01)
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Modeling and Analysis of Biological Systems Study Section (MABS)
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Preusch, Peter C
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Worcester Polytechnic Institute
Schools of Engineering
United States
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Sharma, Ity; Kaminski, George A (2017) Using polarizable POSSIM force field and fuzzy-border continuum solvent model to calculate pK(a) shifts of protein residues. J Comput Chem 38:65-80
Cvitkovic, John P; Kaminski, George A (2017) Developing multisite empirical force field models for Pt(II) and cisplatin. J Comput Chem 38:161-168
Kaminski, George A (2014) Computational Studies of the Effect of Shock Waves on the Binding of Model Complexes. J Chem Theory Comput 10:4972-4981
Li, Xinbi; Ponomarev, Sergei Y; Sigalovsky, Daniel L et al. (2014) POSSIM: Parameterizing Complete Second-Order Polarizable Force Field for Proteins. J Chem Theory Comput 10:4896-4910
Li, Xinbi; Ponomarev, Sergei Y; Sa, Qina et al. (2013) Polarizable simulations with second order interaction model (POSSIM) force field: developing parameters for protein side-chain analogues. J Comput Chem 34:1241-50
Ponomarev, Sergei Y; Sa, Qina; Kaminski, George A (2012) Effects of lysine substitution on stability of polyalanine alpha-helix. J Chem Theory Comput 8:4691-4706
Sharma, Ity; Kaminski, George A (2012) Calculating pKa values for substituted phenols and hydration energies for other compounds with the first-order Fuzzy-Border continuum solvation model. J Comput Chem 33:2388-99
Click, Timothy H; Ponomarev, Sergei Y; Kaminski, George A (2012) Importance of electrostatic polarizability in calculating cysteine acidity constants and copper(I) binding energy of Bacillus subtilis CopZ. J Comput Chem 33:1142-51
Click, Timothy H; Liu, Aibing; Kaminski, George A (2011) Quality of random number generators significantly affects results of Monte Carlo simulations for organic and biological systems. J Comput Chem 32:513-24
Ponomarev, Sergei Y; Click, Timothy H; Kaminski, George A (2011) Electrostatic polarization is crucial in reproducing Cu(I) interaction energies and hydration. J Phys Chem B 115:10079-85

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