Comp Chem Research Developments

September 14, 2005

PM3_BP : A new semiempirical quantum model for hydrogen bonded nucleic acid base pairs

The accurate calculation of the electronic structure and associated properties of biomolecules remains an important challenge in computational biochemistry. Unfortunately, for many biological applications, accurate ab initio methods are thwarted by the computational cost associated with the inherently large system size, broad temporal domain or high degree of phase-space sampling required by the problem. Semiempirical quantum methods have traditionally not been considered to be of sufficient accuracy for biological chemistry, largely because their development has focused on more general ground-state thermochemical applications. Due to their immense computational advantage, there has been a recent resurgence in interest to develop new semiempirical quantum models specifically designed to provide high accuracy for biological systems.

The interaction of nucleic acid bases in DNA and RNA structures play an integral role in macromolecular structure and function. Hydrogen bonding interactions between nucleic acid base pairs is vital to the integrity of duplex DNA and responsible for transfer of genetic information. An accurate description of nucleic acid base pairs requires a proper description of the dipole moments and delocalization of π-bonds of the individual bases, and of intermolecular hydrogen bonding. These features are not adequately reproduced by any of the standard semiempirical models.

Recently, the research groups of Professor Darrin York and graduate student Timothy Giese of the Department of Chemistry, in collaboration with Professor Christopher Cramer and Ed Sherer (now at Rib-X Pharmaceuticals) have developed a new semiempirical quantum model specifically designed to provide very high accuracy for hydrogen-bonded nucleic acid base pairs (Fig. 1).

ATwc CGwc ATh CGrh

Figure 1. Superimposed root-mean-squared fit of PM3BP (lighter colors) geometry optimized structures to DFT mPWPW91/MIDI! structures (darker colors) for several representative structures. The notations AT and CG refer to adenine-thymine and cytosine-guanine base pairs, respectively. WC, RWC, H, RH, refer to Watson-Crick, reverse Watson-Crick, Hoogsteen, and reverse Hoogsteen hydrogen bonding arrangements, respectively.

Figure 2. Regression of semiempirical and DFT mPWPW91/MIDI! binding enthalpies for nucleic acid base dimers with experimental (x-axis) values.

The PM3_BP method delivers accuracy comparable (or exceeding) that of high-level density-functional methods for 3-4 orders of magnitude reduction in computational cost (Fig. 2). The results have been published in an upcoming article in the new ACS  theory journal JCTC. These results make an important contribution toward the design of next-generation semiempirical quantum models for biological molecules that can be used in linear-scaling electronic structure and hybrid quantum mechanical/molecular mechanical simulations.