Although transcription is of central importance to cell survival, only few antimicrobial agents have been directed towards RNA polymerase (RNAP) enzyme. For example, short peptide inhibitors act by binding within the nucleotide entry channel and blocking the path of the nucleotide triphosphate (NTP) to the active site. We are interested in blocking of bacterial RNAP active sites directly ? using analogs of NTPs. Such approach is popular in the case of viral infections (including HIV).

A number of high-resolution structures for bacterial RNAPs have recently been solved. These structures give valuable insights into the structure and functions of RNAP, and the information can be applied (using homology modeling) onto many species due to similarities between their RNAP structures. Molecular dynamics simulations of biopolymers starting from high-resolution crystal structures supplemented with explicit solvent molecules raise a possibility to perform structural studies of bio-molecules in solution. Ab initio calculations are used for developing and refining of empirical force-fields to enable molecular dynamics simulations with chemically modified systems.

Here, we present results of homology modeling (using MODELLER software package), ab initio calculations (using GAUSSIAN03 and TURBOMOLE software package) and molecular dynamics simulations (using NAMD software package) of RNAPs in complex with nucleic acids (template DNA strand, RNA transcript, NTP ? either natural or chemically modified). These interactions were investigated with a view of designing of small NTP analogs to act as bacterial RNAP inhibitors.

Support from the Ministry of Education, Youth and Sports of the Czech Republic (Project No. MSM 0021620835 and Project No. NPVII 2B06065) is gratefully acknowledged.