Research

Designed by Sergei Y. Ponomarev sponomarev@wpi.edu and George A. Kaminski gkaminski@wpi.edu

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	Research I am a computational physical chemist. My research is dedicated to building bridges between robust physical principles behind molecular interactions and computer simulations of physical, biophysical and organic interest. Thus, much of our work is in the areas of force field development and applications. Simulations of proteins is a very important biomedical research area since proteins play critical role in a large number of biological phenomena, both benign and harmful. But the results of these simulations are only as good as the quality of the "nuts and bolts" used in modeling the molecules, and these "nuts and bolts" are what force fields are. Our work is focused in understanding the underlying mechanics of the molecular interactions, creating tools for simulating big systems and on testing and applying such tools. One of the important directions we have been pursuing is in developing polarizable force fields. Accuracy of energy calculations often depend critically upon explicit representation of many-body interactions. For example, we have demonstrated that it is possible to obtain protein pKa values within 0.6 - 0.7 pH units from the corresponding experimental values when our polarizable force field is used, while fixed-charges counterparts produce errors which are several times greater: Reproducing basic pKa values for turkey ovomucoid third domain using a polarizable force field. Click TH, Kaminski GA. J Phys Chem B. 2009 Jun 4;113(22):7844-50.PMID: 19432439 [PubMed - indexed for MEDLINE] Electrostatic polarization is crucial for reproducing pKa shifts of carboxylic residues in Turkey ovomucoid third domain. Macdermaid CM, Kaminski GA. J Phys Chem B. 2007 Aug 2;111(30):9036-44. Epub 2007 Jun 28.PMID: 17602581 [PubMed - indexed for MEDLINE] We have also demonstrated that including explicit polarization can be necessary to obtain correct protein binding energies, especially when metal ions are involved. IN some cases, fixed-charges force fields do not even predict a thermodynamically stable binding, while explicit polarization yields a qualitatively correct picture: Importance of electrostatic polarizability in calculating cysteine acidity constants and copper(I) binding energy of Bacillus subtilis CopZ. Click TH, Ponomarev SY, Kaminski GA. J Comput Chem. 2012 Apr 30;33(11):1142-51. doi: 10.1002/jcc.22944. Epub 2012 Feb 27.PMID: 22370900 [PubMed - indexed for MEDLINE] Metal ions play a significant role in biophysical processes, but modeling of heavy metal ions with force fields has been lagging and the methods employed are not always very accurate. We are trying to contribute to ameliorating the situation by including accurate models of such ions in our polarizable force fields. Our work in building, improving and applying explicit polarization has lead us to creation of POSSIM (Polarizable Simulations with Second order Interaction Model) software suit and parameter set. This software utilizes a fast polarizable methodology. It permits to cut the computational cost of using polarization by about an order of magnitude. POSSIM is available for download at this website here. Some related references are: Polarizable Simulations with Second order Interaction Model (POSSIM) force field: Developing parameters for side-chain analogues Li X, Ponomarev SY, Sa Q, Sigalovsky DL, Kaminski GA. J Comput Chem, accepted for publication [PubMed ID NIHMS444236]. Effects of Lysine Substitution on Stability of Polyalanine alpha-Helix Ponomarev SY, Sa Q, Kaminski GA. J Chem Theory Comput. 2012; 8(11): 4691-4706. [PubMed - pending] Polarizable Simulations with Second order Interaction Model (POSSIM) force field: Developing parameters for alanine peptides and protein backbone. Ponomarev SY, Kaminski GA. J Chem Theory Comput. 2011 May 10;7(5):1415-1427.PMID: 21743799 [PubMed] Polarizable Simulations with Second order Interaction Model - force field and software for fast polarizable calculations: Parameters for small model systems and free energy calculations. Kaminski GA, Ponomarev SY, Liu AB. J Chem Theory Comput. 2009 Oct 5;5(11):2935-2943.PMID: 20209038 [PubMed] The latest version of POSSIM includes capabilities for using a novel Fuzzy-Border continuum solvation model. At this point, this technique can be used with fixed-charges systems. We are working on extending it to be compatible with the polarizable POSSIM force field. The methodology and results of initial applications are described in the following paper: Calculating pK(a) values for substituted phenols and hydration energies for other compounds with the first-order fuzzy-border continuum solvation model. Sharma I, Kaminski GA. J Comput Chem. 2012 Nov 15;33(30):2388-99. doi: 10.1002/jcc.23074. Epub 2012 Jul 19.PMID: 22815192 [PubMed - in process] Another research area in my lab is in studying protein and protein-ligand behavior under mechanical influence. For example, we proposed a mechanism which explains induction of apoptosis by low-intensity ultrasound irradiation of cancer cells. This study involved computational investigation of complexes of cross-linked apoptosis inhibitors (XIAP) with the caspase protein and a small molecular antagonist: Computational Studies of the X-Link Inhibitor of Apoptosis Complex Formation with Caspase-9 and a Small Antagonist Kaminski GA. J Chem Theory Comput. 2008; 4(5): 847-854. Overall, the goal of our research is to bring the combined power of robust physical theory and modern computers into solving chemical and biochemical problems with a high level of accuracy. Current Funding National Institutes of Health R01 grant R01 GM074624, Protein simulations with a fast polarizable force field (PI - George Kaminski, total amount - $1,365,000).

Current Funding