ELECTRONIC STRUCTURE CALCULATIONS OF HYDROGEN BONDING IN BIOLOGICAL MACROMOLECULES
EMSL Project ID
3443
Abstract
Hydrogen bonding interactions play a crucial role in stabilizing native protein conformations, and in determining specifity and stability of protein-ligand docked complexes. In force field calculations of biological macromolecules, hydrogen bonds are often represented by simplified phenomenological models based on elec-trostatic (dipole-dipole) interactions, protein database statistics, or simple analytical expressions employed to reproduce angular dependence of hydrogen bonding interactions.Calculations utilizing such simplified models are computationally efficient;
they allow testing and refinement on large datasets of folded protein structures.
However, they are unable to model such important effects as hydrogen bonding
cooperativity, systematic differences in hydrogen bonds present in different secondary structure elements, and the polarization effects brought about by inter-molecular hydrogen bond formation. Another aspect of this research project will be to test the limits of applicability of non-polarizable force fields when polypep-tide conformation is changed, or intermolecular hydrogen bonds are formed in a test system. In order to investigate these issues, we propose to carry out ab initio quantum chemical computations of representative polypeptide conformations found in experimentally determined protein structures.
We will use the NWChem package, which is the computational quantum chemistry
software originally developed at PNNL. This software utilizes parallel scala-bility of PNNL machines, which will allow us to investigate longer polypeptides with 40 to 60 non-hydrogen atoms and multiple hydrogen bonds.
The main goal of this research is to develop a quantum mechanical model of hydrogen bonds which will be more accurate than existing phenomenological models, and which will elucidate important quantum mechanical aspects of hydrogen bonding interactions in biological macromolecules. The computational power available at PNNL will make extensive tests of this model possible. These tests are necessary
in establishing the accuracy of the hydrogen bonding model obtained through
ab initio computations.
If an accurate quantum mechanical model of hydrogen bonding interactions is
developed as a result of this project, it will help improve on approximate results obtained through classical force field simulations, and in many cases understand the extent of their validity. This, in turn, will prove invaluable in such important and diverse fields of computational and molecular biology as ab initio protein structure determination, protein folding dynamics, and protein-protein and protein-small molecule interactions.
Project Details
Project type
Exploratory Research
Start Date
2003-03-21
End Date
2004-03-16
Status
Closed
Released Data Link
Team
Principal Investigator
Team Members