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Ribosomes are macromolecular complexes responsible for the translation of the mRNA into protein. These complexes consist of two subunits: the large 50S subunit and the small 30S subunit, both of which are composed of RNA and protein constituents. During translation, the large and small subunits associate to form an active ribosome. Recently, high-resolution structures of the 50S subunit from Haloarcula marismortui (27) and the 30S subunit from Thermus thermophilus (28, 29) were solved by x-ray crystallography. These structures present a unique opportunity to examine the electrostatic potential of large ribonucleoprotein complexes.
The protonated 30S structure consists of more than 88,000 atoms and roughly spans a 200-Å-long cubic box. Using APBS on 343 processors of the NPACI Blue Horizon, LPBE was solved to give the electrostatic potential of the small ribosomal subunit at 0.41-Å resolution. Calculations also were performed on the protonated 50S subunit structure, which consisted of 94,854 atoms and has similar dimensions to the 30S subunit. The electrostatic potential of the large subunit was obtained at 0.45-Å resolution by using APBS to solve the LPBE on 343 processors of the Blue Horizon. Both systems were solved by using the parallel focusing algorithm: each processor first solved a coarse problem defined by a 973 mesh covering the entire problem domain, and the solved the LPBE on a 973 mesh covering the particular subset of the global problem. Examination of the electrostatic potential mapped to the molecular surfaces of the 30S (Fig. 5) and 50S (Fig. 6) reveals large areas of negative potential with smaller regions of positive potential corresponding to some of the proteins implicated in binding of the 30S and 50S subunits to form the active ribosomal complex (27, 29-31). Not surprisingly, the potential surface maps between the two subunits exhibit qualitative electrostatic complementarity. Despite the fact that the 30S and 50S structures are from distinct species that thrive in very different environments, such comparisons of electrostatic potential are not unwarranted. Formation of active ribosomal complexes has been observed by using subunits from different species (32, 33), indicating some evolutionary conservation of the elements involved in subunit association.
Fig. 5 b and d shows the electrostatic potential mapped to the 30S subunit molecular surface. As evidenced by the 30S structure (Fig. 5 a and c), regions of positive potential typically correspond to protein components of the small subunit or cocrystallized counterions. Of particular interest is the active site of the 30S subunit, shown in Fig. 5 a and b. There are interesting variations in the electrostatic potential near regions of antibiotic binding (34) and the A, P, and E tRNA binding sites (29, 34). For example, the codon binding sites and "platform region" (protuberance on the right side of Fig. 5 a and b) are surrounded by regions of positive potential, which could help stabilize complexes of the ribosome with mRNA and tRNA. However, more quantitative calculations will be needed to fully explore these hypotheses.
The electrostatic potential of the 50S subunit is shown in Fig. 6 b and d. Like the small subunit, the electrostatic surface potential is largely negative, with scattered regions of positive potential typically associated with ribosomal proteins. Some of the most interesting aspects of this data set are the regions of positive potential on the 50S "crown" (see upper protuberance in Fig. 6 a and b), which correspond to proteins of the large subunit involved in tRNA binding. Specifically, these positive regions are due to proteins L44e, L5, and L10e (see Fig. 6a), which have been implicated in tRNA binding to the 50S subunit (35), and contribute large regions of positive potential to the molecular surface in the upper portions of the A, P, and E tRNA binding sites. Furthermore, the P-loop (shown as blue spheres in Fig. 6a), an important component of the 50S P-site (35, 36), shows significant positive surface potential due to a nearby Mg2+ ion. These areas of positive potential may provide stabilizing interactions with mRNA or tRNA bound to the ribosomal complex during translation. However, as with the 30S calculations, more detailed work is required to accurately resolve the role of electrostatics in tRNA and mRNA binding to the 50S subunit.
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