Radial scan of the molecular electrostatic potential of RNA double helices: an application to the enzyme-tRNA recognition.

We introduced a method to characterize quantitatively the molecular electrostatic potential (MEP) of the minor and major grooves of base pairs located at nucleic acid double helices. By means of a radial MEP scan, we obtained a n-tuple of potential values corresponding to each groove, which can be analyzed by plotting the MEP values as a function of the angle in the radial scan. We studied base pairs of two different tRNAs, relevant in the recognition process with their cognate aminoacyl tRNA synthetases (aaRSs), in order to correlate their electrostatic behavior with the corresponding aminoacylation activity. We analyzed the first three base pairs of the Escherichia coli tRNA(Ala) acceptor stem, finding several cases where the MEP profiles obtained from the plots are in agreement with the reported aminoacylation activities. Additionally, a non-hierarchical clustering performed over the MEP n-tuples resulted in meaningful classifications that correlate with the activity and with the predicted stereochemistry of the reaction. We also studied the first two base pairs of the E. coli tRNA(Thr) acceptor stem but constraining the analysis to the angle intervals that seem relevant for the binding sites of the enzyme. These intervals were deduced from the ThrRS-tRNA(Thr) complex crystal structure. In this case, we also found a good agreement between the MEP profiles and the activity, supporting the idea that the tRNA identity elements function is to allow an optimal electrostatic complementarity between the aminoacyl-tRNA synthetase and the tRNA.

CARACTERIZACIÓN DEL TALLO ACEPTOR DEL tARN MEDIANTE DESCRIPTORES LOCALES BASADOS EN CARGAS PARCIALES / tRNA ACCEPTOR STEM CHARACTERIZATION BY MEANS OF LOCAL DESCRIPTORS BASED ON PARTIAL CHARGES / CARACTERIZAÇÃO DO TALO ACEITADOR DO tRNA MEDIANTE DESCRITORES LOCAIS BASEADOS EM CARGAS PARCIAIS

En este trabajo se caracteriza la distribución de carga del tallo aceptor del tARN, considerando todas las posibles combinaciones de pares Watson-Crick. El estudio se realizó con 256 fragmentos moleculares de 10 nucleótidos que modelan los tres primeros pares del tallo aceptor, la base diferenciadora y el extremo CCA. Para caracterizar los nucleótidos se proponen dos descriptores locales basados en la distribución de carga de la base nitrogenada de cada nucleótido, los cuales se calculan a partir de las cargas parciales de Mulliken obtenidas de cálculos HF/6-31G. La caracterización y clasificación de los tallos según estos descriptores mostró cómo la base diferenciadora tiene un comportamiento particular respecto a los demás nucleótidos del tallo y una fuerte influencia sobre el extremo CCA. La clasificación de nueve variaciones del tallo aceptor del tARNAla mostró una buena relación estructura-actividad que pone en evidencia la bondad de los descriptores propuestos para caracterizar de manera local la distribución de carga de estas biomoléculas.

In this work the charge distribution of the tRNA acceptor stem is characterized, considering all the possible Watson- Crick base pair combinations. 256 RNA fragments modeled by 10 nucleotides were used in order to model the first three pairs of the acceptor stem, the discriminator base and the CCA end. We propose two local charge descriptors based on the charge distribution of the nitrogenated base to characterize each nucleotide. These descriptors were computed from atomic partial charges derived from HF/6-31G calculations. From the characterization and classification of the stems according to the proposed descriptors, we found a special behavior for the discriminator base (in contrast to the other positions) and a strong effect of this position on the CCA end. The classification of nine variations of the tRNAAla acceptor stem showed a good structure-activity relationship that makes evident the usefulness of the proposed descriptors to characterize the local charge distributions of these biomolecules.

Nesse estudo é caracterizada a distribuição da carga do talo aceitador considerando- se todas as combinações possíveis dos pares Watson-Crick. O estudo realizouse com 256 fragmentos moleculares dos 10 nucleotídeos que modelam os três primeiros pares do talo aceitador, a base diferenciadora e o extremo CCA. Com o intuito de caracterizar cada nucleotídeo, foram propostos dois descritores locais baseados na distribuição de carga da base nitrogenada de cada nucleotídeo, os quais se calculam a partir das cargas parciais de Mulliken obtidas de cálculos HF/6-31G. A caracterização e classificação dos talos segundo esses descritores demonstrou um particular comportamento da base diferenciadora em relação aos demais nucleotídeos do talo e uma forte influência sobre o extremo CCA. A classificação de nove variações do talo aceitador do tRNA mostrou uma boa relação estrutura-atividade que colocam em evidência a utilidade dos descritores propostos para caracterizar de maneira local a distribuição de carga dessas bio-moléculas.

Graph theoretical similarity approach to compare molecular electrostatic potentials.

In this work we introduce a graph theoretical method to compare MEPs, which is independent of molecular alignment. It is based on the edit distance of weighted rooted trees, which encode the geometrical and topological information of Negative Molecular Isopotential Surfaces. A meaningful chemical classification of a set of 46 molecules with different functional groups was achieved. Structure--activity relationships for the corticosteroid binding affinity (CBG) of 31 steroids by means of hierarchical clustering resulted in a clear partitioning in high, intermediate, and low activity groups, whereas the results from quantitative structure--activity relationships, obtained from a partial least-squares analysis, showed comparable or better cross-validated correlation coefficients than the ones reported for previous methods based solely in the MEP.