What are the forces that shape the structure of prokaryotic genomes: the order of genes, their proximity, and their orientation? Coregulation and coordinated horizontal gene transfer are believed to promote the proximity of functionally related genes and the formation of operons. However, forces that influence the structure of the genome beyond the level of a single operon remain unknown. Here, we show that the biophysical mechanism by which regulatory proteins search for their sites on DNA can impose constraints on genome structure. Using simulations, we demonstrate that rapid and reliable gene regulation requires that the transcription factor (TF) gene be close to the site on DNA the TF has to bind, thus promoting the colocalization of TF genes and their targets on the genome. We use parameters that have been measured in recent experiments to estimate the relevant length and times scales of this process and demonstrate that the search for a cognate site may be prohibitively slow if a TF has a low copy number and is not colocalized. We also analyze TFs and their sites in a number of bacterial genomes, confirm that they are colocalized significantly more often than expected, and show that this observation cannot be attributed to the pressure for coregulation or formation of selfish gene clusters, thus supporting the role of the biophysical constraint in shaping the structure of prokaryotic genomes. Our results demonstrate how spatial organization can influence timing and noise in gene expression.diffusion ͉ genetics ͉ genomics ͉ protein-DNA interactions ͉ spatial effects T he colocalization of prokaryotic transcription factor (TF) genes and their binding sites is known from the pioneering work of Jacob and Monod (1) on the lactose operon and has been shown to be widespread (2-4) and essential for the formation of regulatory motifs (5). Some have hypothesized that TF-binding site colocalization is advantageous, in part, because it could expedite a TF's search for its site (2, 5-7) (the rapid search hypothesis). In prokaryotes, this speed-up by colocalization is possible because transcription and translation are coupled spatially and temporally. Therefore, TFs are synthesized near their genes and can rapidly bind colocalized sites (Fig. 1A). The arrival time of a TF to its site ultimately controls the timing of gene regulation, whereas fluctuations in the arrival time can lead to bursts of gene activity and noise in gene regulation. The rapid search hypothesis suggests that colocalization is favorable because expediting TF arrival makes regulation faster and more reliable.Both experimentally (see ref.8 for an overview) and theoretically (9-13), many have studied the broader question: how can a TF find its cognate site on DNA among Ϸ10 7 decoy sites in a fraction of a minute while moving in the crowded environment of the cell and hampered by other DNA-bound proteins? The general model of the process includes 3D spatial diffusion of the TF through the cell volume and 1D sliding of a TF along DNA. According to this m...

We present a computational tool, eReaxFF, for simulating explicit electrons within the framework of the standard ReaxFF reactive force field method. We treat electrons explicitly in a pseudoclassical manner that enables simulation several orders of magnitude faster than quantum chemistry (QC) methods, while retaining the ReaxFF transferability. We delineate here the fundamental concepts of the eReaxFF method and the integration of the Atom-condensed Kohn-Sham DFT approximated to second order (ACKS2) charge calculation scheme into the eReaxFF. We trained our force field to capture electron affinities (EA) of various species. As a proof-of-principle, we performed a set of molecular dynamics (MD) simulations with an explicit electron model for representative hydrocarbon radicals. We establish a good qualitative agreement of EAs of various species with experimental data, and MD simulations with eReaxFF agree well with the corresponding Ehrenfest dynamics simulations. The standard ReaxFF parameters available in the literature are transferrable to the eReaxFF method. The computationally economic eReaxFF method will be a useful tool for studying large-scale chemical and physical systems with explicit electrons as an alternative to computationally demanding QC methods.

KNOTS (http://knots.mit.edu) is a web server that detects knots in protein structures. Several protein structures have been reported to contain intricate knots. The physiological role of knots and their effect on folding and evolution is an area of active research. The user submits a PDB id or uploads a 3D protein structure in PDB or mmCIF format. The current implementation of the server uses the Alexander polynomial to detect knots. The results of the analysis that are presented to the user are the location of the knot in the structure, the type of the knot and an interactive visualization of the knot. The results can also be downloaded and viewed offline. The server also maintains a regularly updated list of known knots in protein structures.