Commun. Comput. Phys.,
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Volume 3.


Salt Dependent Association of Novel Mutants of TATA-Binding Proteins to DNA: Predictions from Theory and Experiments

Johan H. Bredenberg 1, Marcia O. Fenley 2*

1 Institute of Molecular Biophysics, Florida State University, Tallahassee, FL 32306, USA.
2 Institute of Molecular Biophysics, Florida State University, Tallahassee, FL 32306, USA; and Department of Physics, Florida State University, Tallahassee, FL 32306, USA.

Received 11 December 2007; Accepted (in revised version) 27 January 2008
Available online 18 February 2008

Abstract

The nonlinear Poisson-Boltzmann predictions of the salt-dependent association of proteins to DNA, SK$_\text{pred}$, are fairly insensitive to the choice of atomic charges, radii, interior dielectric constant and treatment of the boundary between a biomolecule and the solvent. In this study we show that the SK$_\text{pred}$ is highly correlated with the conformational adaptability of the partners involved in the biomolecular binding process. This is demonstrated for the wild-type and mutant forms of the archaeon \emph{Pyrococcus woesi} TATA-binding protein ({\it Pw}TBP) in complex with DNA, on which we performed molecular mechanics energy minimizations with different protocols, and molecular dynamics simulations and then computed the SK$_\text{pred}$ on the resulting structures. It was found that the inter-molecular non bonded force field energy between the DNA and protein correlates linearly and significantly well with the SK$_\text{pred}$. This correlation encompasses the wild-type and mutant variants of the {\it Pw}TBP and provides us with a quick way to estimate the SK$_\text{pred}$ from a large ensemble of structures generated with Molecular Dynamics or Monte Carlo simulations. The corresponding experimental SK$_\text{obs}$ should also correlate with the inter-molecular non bonded force field energy between the protein and DNA, given that the underlying mechanisms in binding and salt-dependent effects are in fact the main contributors in the association of proteins/peptides to nucleic acids. We show that it is possible to fit experiments versus the inter-molecular non bonded force field energy between the protein and DNA, and use this relation to predict the SK$_\text{obs}$ in absolute numbers. Thus, we present two novel approaches to estimate both the SK$_\text{pred}$ and the SK$_\text{obs}$ for \emph{in silico} modelled {\it Pw}TBP novel mutants and even for TBPs from other organisms. This is a simple but powerful tool to suggest new experiments on the TBP-DNA type of macromolecular assemblies. We conclude by suggesting some mutants and a possible biological interpretation of how changes in solvent salinity affect the binding of proteins to DNA.

AMS subject classifications: 35Q80, 92C05, 92C40, 65N06

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Key words: Poisson-Boltzmann equation, electrostatics, salt dependence, binding, molecular mechanics, DNA, TATA binding proteins.

*Corresponding author.
Email: jbreden@sb.fsu.edu (J. H. Bredenberg), mfenley@sb.fsu.edu (M. O. Fenley)
 

The Global Science Journal