Computational Simulation Strategies for Analysis of Multisubunit RNA Polymerases

Multisubunit RNA polymerase (RNAP) mechanisms present challenges for current computational techniques because of their large size, complications of simulating nucleic acids and metals, and also dynamic aspects of the system. The purpose of this review is to discuss computational methods that have been applied to RNAPs and to evaluate the insight gained. Furthermore, this review seeks to anticipate some future approaches expected to give additional understanding. Because RNAPs pose challenges to available computation technology, these studies may necessitate improvements in methods and hardware applied to very large multiatom systems that include protein and nucleic acid components. Other reviews on RNAP structure/function have recently appeared but generally with a different focus.1 This review was developed on the basis of collaborations involving the Feig, Cukier, Burton, Kashlev, and Coulombe laboratories. The attempt has been to combine sophisticated computational analyses with biochemical and genetic structure/function studies of multisubunit RNAPs. The hope was that integrating these broad approaches might enrich the science, leading to a deeper description of a complex, templated polymerization mechanism central and global in known living systems. So far, this collaborative approach has led to advances in understanding and an indication that going back and forth between simulation and experiment should prove an incisive approach to a very big problem in biology. This review can be viewed as a progress report with an eye to a bright and revealing future. In section 13, particular emphasis is placed on quantum chemistry (QC) methods to analyze details of RNAP and DNA polymerase (DNAP) mechanisms. This section is expanded in detail relative to others because the 2-Mg mechanism is currently a subject of great general interest, but the language and methods of QC may not be easily accessible to all who may be interested. We attempt an accessible presentation of a sophisticated and developing field.

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