TABASCO: A single molecule, base-pair resolved gene expression simulator.
BACKGROUND
Experimental studies of gene expression have identified some of the individual molecular components and elementary reactions that comprise and control cellular behavior. Given our current understanding of gene expression, and the goals of biotechnology research, both scientists and engineers would benefit from detailed simulators that can explicitly compute genome-wide expression levels as a function of individual molecular events, including the activities and interactions of molecules on DNA at single base pair resolution. However, for practical reasons including computational tractability, available simulators have not been able to represent genome-scale models of gene expression at this level of detail.


RESULTS
Here we develop a simulator, TABASCO http://openwetware.org/wiki/TABASCO, which enables the precise representation of individual molecules and events in gene expression for genome-scale systems. We use a single molecule computational engine to track individual molecules interacting with and along nucleic acid polymers at single base resolution. Tabasco uses logical rules to automatically update and delimit the set of species and reactions that comprise a system during simulation, thereby avoiding the need for a priori specification of all possible combinations of molecules and reaction events. We confirm that single molecule, base-pair resolved simulation using TABASCO (Tabasco) can accurately compute gene expression dynamics and, moving beyond previous simulators, provide for the direct representation of intermolecular events such as polymerase collisions and promoter occlusion. We demonstrate the computational capacity of Tabasco by simulating the entirety of gene expression during bacteriophage T7 infection; for reference, the 39,937 base pair T7 genome encodes 56 genes that are transcribed by two types of RNA polymerases active across 22 promoters.


CONCLUSIONS
Tabasco enables genome-scale simulation of transcription and translation at individual molecule and single base-pair resolution. By directly representing the position and activity of individual molecules on DNA, Tabasco can directly test the effects of detailed molecular processes on system-wide gene expression. Tabasco would also be useful for studying the complex regulatory mechanisms controlling eukaryotic gene expression. The computational engine underlying Tabasco could also be adapted to represent other types of processive systems in which individual reaction events are organized across a single spatial dimension (e.g., polysaccharide synthesis).
Kosuri
Sriram
S
Department of Biological Engineering, Massachusetts Institute of Technology, 77 Massachusetts Ave,, Cambridge, MA 02139 USA. skosuri@mit.edu
Kelly
Jason R
JR
Endy
Drew
D
D017123:Bacteriophage T7 / Q000235:genetics / Q000378:metabolism; D020029:Base Pairing; D001665:Binding Sites; D003198:Computer Simulation; D012321:DNA-Directed RNA Polymerases / Q000378:metabolism; D004926:Escherichia coli / Q000235:genetics / Q000378:metabolism; D015870:Gene Expression; D020869:Gene Expression Profiling / Q000379:methods*; D005786:Gene Expression Regulation; D016681:Genome, Fungal; D051188:Knowledge Bases; D016015:Logistic Models; D050436:Regulatory Elements, Transcriptional; D012680:Sensitivity and Specificity; D017422:Sequence Analysis, DNA; D012985:Software Design; D014157:Transcription Factors / Q000737:chemistry / Q000235:genetics; D014764:Viral Proteins / Q000378:metabolism
D014157:Transcription Factors; D014764:Viral Proteins; C062210:bacteriophage T7 RNA polymerase; D012321:DNA-Directed RNA Polymerases