Our research is designed to address one of the long-standing grand challenges in theoretical and computational chemistry, namely molecular modeling of chemical reactions in polyatomic systems. The new theoretical and computational tools developed in this work will allow us to solve important fundamental dynamics and mechanistic problems in chemistry, quantum biology, and in material science.
Development of New Direct Dynamical Methods
Theoretical and computational chemistry has been gaining a vital role in the competitive fields of drug and materials design. In the race to design novel compounds, just knowing a reasonably accurate molecular structure of the target system already has obvious advantages. However, the ultimate goal for computer-aided molecular design is the ability to model chemical reactions involving the target system. To do this, we need a potential energy surface that can adequately describe the energetics of bond breaking and forming in the reacting system. Conventionally, it is represented by an analytical function. But the development of such a potential energy function is not a simple task, since its functional forms and the procedure for fitting these forms to known experimental or electronic structure data depend largely on the investigator's own intuition. Consequently, molecular modeling of chemical reactions remains a challenging problem in theory, despite the rapid improvement in computer technology.
We have been developing a new approach for calculating reaction paths, free-energy of activation, thermal rate constants and kinetic isotope effects using variational transition state theory and multidimensional semiclassical tunneling methods with electronic information to be calculated directly from density functional theory or ab initio molecular orbital theories. This eliminates the need of an analytical potential energy function. This work includes the development of innovative scalable techniques to carry out such calculations in a distributed computing environment or on massive parallel computers.
We have been applying our direct ab initio dynamics methods to study dynamics and mechanisms of chemical reactions which have importance in the areas of fundamental chemical physics, material science, and biological chemistry. For biological chemistry applications, we are interested in the detailed dynamics of the proton tunneling phenomena in hydrogen bond systems, such as DNA base pairs. Also we are examining the role of solvent in such processes.
Solvent Effects on Structure and Function of Biomolecules
Solvent effects on the structure and function of solutes are not only important for elucidating reaction mechanisms of many organic and bioorganic reactions but are also crucial for molecular drug design. Although many efforts have been devoted to this area, incorporating solvent effects into quantum electronic structure methods in an accurate and yet efficient manner has been challenging. We have been developing a new dielectric continuum solvation model for an arbitrary shape cavity that can be incorporated into both classical and quantum mechanical theories. This solvation model has shown considerable promise with regard to accuracy, efficiency, stability and cost effectiveness. Within the classical approach of this solvation model, our current work attempts to gain insights into structures and functions of biopolymers -- such as studying conformational equilibria of polypeptides and pKa values of proteins. Current projects include implementing analytical first and second energy derivatives of our solvation model within the molecular orbital and density functional theory frameworks. This will allow quantum mechanical studies of solvent effects on solute structures and reaction profiles more efficiently. Works on developing new theories within our quantum mechanical solvation model to study solvent effects on spectroscopic properties, particularly on the NMR shift, IR and electronic absorption, and emission spectra of biomolecules are also underway.
- Le L, Lee E, Schulten K, Truong TN (2009) Molecular modeling of swine influenza A/H1N1, Spanish H1N1, and avian H5N1 flu N1 neuraminidases bound to Tamiflu and Relenza. Version 4. PLoS Curr. 2009 Aug 27 [revised 2011 Jan 3]1: RRN1015.
- Freedman H, Le L, Tuszynski JA, Truong TN (2008) Improving the Performance of the Coupled Reference Interation Site Model (RISM)/Simulation Method for Absolute Free Energy of Solvation. Journal of Physical Chemistry B. 112(8): 2340-8
- Ehlers JE, Rondan NG, Huynh LK, Pham H, Marks M, Truong TN (2007) Theoretical Study of Mechanisms of the Epoxy-Amine Curing Reaction. Macromolecules 40(12): 4370-4377
- Truong TN, Nayak M, Huynh HH, Cook T, Mahajan P, Tran LT, Bharath J, Jain S, Pham HB, Boonyasiriwat C, Nguyen N, Andersen E, Kim Y, Choe S, Choi J, Cheatham TE III, Facelli JC (2006) Computational Science and Engineering Online (CSE-Online): A cyber-infra-structure for scientific computing. Journal of Chemical Information and Modeling 46(3): 971-84
- Wijitkosoom A, Tonmunphean S, Truong TN, Hannongbua S (2006) Structural and dynamical properties of a full-length HIV-1 integrase: molecular dynamics simulations. Journal of Biomolecular Structure and Dynamics 23(6): 613-24