Protoribosome by quantum kernel energy method

Experimental evidence suggests the existence of an RNA molecular prebiotic entity, called by us the “protoribosome,” which may have evolved in the RNA world before evolution of the genetic code and proteins. This vestige of the RNA world, which possesses all of the capabilities required for peptide bond formation, seems to be still functioning in the heart of all of the contemporary ribosome. Within the modern ribosome this remnant includes the peptidyl transferase center. Its highly conserved nucleotide sequence is suggestive of its robustness under diverse environmental conditions, and hence on its prebiotic origin. Its twofold pseudosymmetry suggests that this entity could have been a dimer of self-folding RNA units that formed a pocket within which two activated amino acids might be accommodated, similar to the binding mode of modern tRNA molecules that carry amino acids or peptidyl moieties. Using quantum mechanics and crystal coordinates, this work studies the question of whether the putative protoribosome has properties necessary to function as an evolutionary precursor to the modern ribosome. The quantum model used in the calculations is density functional theory–B3LYP/3–21G*, implemented using the kernel energy method to make the computations practical and efficient. It occurs that the necessary conditions that would characterize a practicable protoribosome—namely (i) energetic structural stability and (ii) energetically stable attachment to substrates—are both well satisfied.A suggestion of a molecular entity, called “protoribosome,” which may have evolved and emerged from an RNA world before a subsequent evolution into the modern protein/nucleic acid world, has been reported (1–3). In contemporary cells the ribosomes translate the genetic information (stored in the DNA) into proteins. Ribosomes are gigantic complexes, which in prokaryotes are built of some 50 proteins and three RNA chains with a total of 4,500 nucleotides. Aptly referred to as the protein factory of all living cells, the ribosome is essential to the contemporary life, and its activity may have been crucial to the formation of life itself. Structural analysis identified an internal RNA region that exists in all known structures (1–5) and has universally conserved sequence (1), which contains the site of peptide bond formation, and thus may well be that of a remaining RNA world entity. Consistent with the findings that the main ribosomal functions—namely, the decoding of the genetic code, the formation of peptide bonds, and the creation of elongating proteins—are performed by ribosomal RNA and with the universality of this region among all kingdoms of life, we proposed that this region is a remnant of a prebiotic chemical entity with catalytic capabilities, and called it the “protoribosome.” Within the otherwise asymmetric ribosome, this region has a unique fold (6) and could have been the link to the modern world (7). It is characterized by a pseudotwofold symmetry with a highly conserved nucleotide sequence and seems to possess all of the assumed prerequisites for the formation of chemical bonds. This semisymmetric object could be a dimer of self-folding RNA units that formed a pocket within which two activated amino acids, as substrates, might be accommodated.A representation of a plausible sequence for spontaneous self-assembly of a protoribosome is shown in Fig. 1 (2). Here, we put forth the use of quantum mechanics to answer the following question: Is the suggested protoribosome structure a plausible reality? One may systematically remove—that is, mathematically—all surrounding parts of the modern ribosome and use the coordinates of a central symmetric pocket for constructing a putative protoribosome. Here we apply quantum mechanics to the structure of that protoribosome. The most fundamental inquiry followed in this article is that of the energetic stability of the proposed protoribosome. This is not presently known. And obviously if the structure is not energetically stable, it is not likely to be able to act as a biological catalyst, as would be required of a protoribosome. The protoribosome contains almost 200 nucleotides, namely thousands of atoms. Ab initio quantum calculations rise in difficulty as a high power of the number of atoms in the system. Therefore, quantum calculation of the protoribosome energy is a complex computational problem. Fortunately we are in possession of a recently discovered kernel energy method (KEM) (8–24), described below, which alleviates dramatically the computational difficulty of ab initio calculations. Importantly the KEM is highly accurate, as well as computationally efficient.Open in a separate windowFig. 1.The scheme by which small, self-folded RNA molecules dimerize to form a symmetrical pocket allowing accommodation of a pair of substrates. The A-site region (Areg) and the P-site region (Preg), respectively, (Upper Left) dimerize (Upper Right) to allow substrate accommodation. Reproduced by permission from ref. 2 Davidovich et al. (2009) Research in Microbiology 160(7):487–492]. Copyright Elsevier Masson SAS.As an example of the large size of systems that can be studied with ab initio KEM, we have applied the method to a Hartree–Fock (HF) calculation of a 33,000-atom protein (16). It is entirely feasible to treat even larger molecules within the context of KEM capabilities. Therefore, we performed an ab initio KEM study of the protoribosome and showed that its existence is quite feasible. Using KEM we address the question of whether the basic symmetric structure of the folded dimer pocket that constitutes the protoribosome suggested previously (4) proves to be quantum mechanically stable. If so, the next question to address is: Can it accommodate a pair of amino acids bound to a chain of a few (1–3) nucleotides, representing the tRNA 3′−end, spatially and energetically? Furthermore, such calculations should indicate the energetic preferences for the length of the nucleotide chain and its correlation to the protoribome size, ranging between 120 and 180. If both questions would be validated quantum mechanically, that would be highly suggestive of the protoribosome as an actual remnant from the RNA world still functioning in the chemistry of life, in the modern DNA/RNA/protein world.