Protein-DNA interactions play an important role in many fundamental biological processes, especially during DNA replication, DNA transcription into RNA, and protein synthesis. Many of these processes are not completely understood and typically involve large molecular assemblies of proteins and nucleic acids. Such systems are difficult to study with conventional simulation methods. We are using implicit solvent methods to study protein-DNA complexes.


While implicit solvent simulations of proteins are well established, implicit solvent simulations of nucleic acids are not as straightforward. Because nucleic acids interact strongly with the surrounding solvent it is not clear whether a continuum electrostatic model is sufficient for describing interactions of nucleic acids with the environment.

First attempts in simulating a short piece of DNA with implicit solvent were not very successful (crystal structure is shown on the left, simulated structure in the center). However, with a careful application of the GBMV method it is possible to run long stable implicit solvent simulations of DNA as can be seen in this movie




We are also testing the application of hybrid explicit/implicit solvation models where some water molecules are represented explicitly as in the picture shown above on the right (waters are shown in purple). We have started to run simulations of DNA with such a hybrid implicit/explicit model as shown in this movie.


One of the applications that we are interested in is post-replication DNA mismatch repair. In particular we are applying computational methods to gain a detailed mechanisitic understanding of the bacterial mismatch recognition protein MutS and its eukaryotic MSH2/MSH6 and MSH2/MSH3 homologs. In the MutS-based repair mechanism, shown schematically below, the initial mismatch recognition by MutS leads to initiation of repair through binding of MutL and then formation of a complex with MutH.


The mechanism of repair initiation upon binding to defective DNA by MutS most likely involves a large-scale conformational change in MutS driven by ATP hydrolysis. We are examining structure, dynamics, and energetics of the MutS-DNA system in order to learn more about this process.


RNA polymerase II is at the very core of biological life transcribing the genetic code from DNA to the mRNA template that is used for protein synthesis. Despite its importance and numerous studies over many years some aspects of the detailed mechanism of RNA synthesis remain unclear. In collaboration with Zach Burton's we are examining the role of ribonucleotides during the translocation step and its relation to transcription fidelity in RNA polymerase II.

The movie below shows the simulation of a proposed new mechanism, where nucleotides bind to the template DNA downstream from the catalytic site.