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Previous issue date: 2012-03-02 === Coordena??o de Aperfei?oamento de Pessoal de N?vel Superior === In this dissertation, the theoretical principles governing the molecular modeling were applied for
electronic characterization of oligopeptide α3 and its variants (5Q, 7Q)-α3, as well as in the quantum
description of the interaction of the aminoglycoside hygromycin B and the 30S subunit of bacterial
ribosome. In the first study, the linear and neutral dipeptides which make up the mentioned
oligopeptides were modeled and then optimized for a structure of lower potential energy and
appropriate dihedral angles. In this case, three subsequent geometric optimization processes, based
on classical Newtonian theory, the semi-empirical and density functional theory (DFT), explore the
energy landscape of each dipeptide during the search of ideal minimum energy structures. Finally,
great conformers were described about its electrostatic potential, ionization energy (amino acids),
and frontier molecular orbitals and hopping term. From the hopping terms described in this study, it
was possible in subsequent studies to characterize the charge transport propertie of these peptides
models. It envisioned a new biosensor technology capable of diagnosing amyloid diseases, related to
an accumulation of misshapen proteins, based on the conductivity displayed by proteins of the
patient. In a second step of this dissertation, a study carried out by quantum molecular modeling of
the interaction energy of an antibiotic ribosomal aminoglicos?dico on your receiver. It is known that
the hygromycin B (hygB) is an aminoglycoside antibiotic that affects ribosomal translocation by direct
interaction with the small subunit of the bacterial ribosome (30S), specifically with nucleotides in
helix 44 of the 16S ribosomal RNA (16S rRNA). Due to strong electrostatic character of this
connection, it was proposed an energetic investigation of the binding mechanism of this complex
using different values of dielectric constants (ε = 0, 4, 10, 20 and 40), which have been widely used to
study the electrostatic properties of biomolecules. For this, increasing radii centered on the hygB
centroid were measured from the 30S-hygB crystal structure (1HNZ.pdb), and only the individual
interaction energy of each enclosed nucleotide was determined for quantum calculations using
molecular fractionation with conjugate caps (MFCC) strategy. It was noticed that the dielectric
constants underestimated the energies of individual interactions, allowing the convergence state is
achieved quickly. But only for ε = 40, the total binding energy of drug-receptor interaction is
stabilized at r = 18A, which provided an appropriate binding pocket because it encompassed the
main residues that interact more strongly with the hygB - C1403, C1404, G1405, A1493, G1494,
U1495, U1498 and C1496. Thus, the dielectric constant ≈ 40 is ideal for the treatment of systems
with many electrical charges. By comparing the individual binding energies of 16S rRNA nucleotides
with the experimental tests that determine the minimum inhibitory concentration (MIC) of hygB, it is
believed that those residues with high binding values generated bacterial resistance to the drug
when mutated. With the same reasoning, since those with low interaction energy do not influence
effectively the affinity of the hygB in its binding site, there is no loss of effectiveness if they were
replaced. === Nessa disserta??o, os princ?pios te?ricos que regem a Modelagem Molecular foram aplicados na
caracteriza??o eletr?nica do oligopept?deo α3 e seus variantes (5Q,7Q)-α3, como tamb?m na
descri??o qu?ntica da intera??o do aminoglicos?deo higromicina B e a subunidade 30S do ribossomo
bacteriano. No primeiro estudo, os dipept?deos lineares e neutros constituintes das biomol?culas
mencionados foram modelados e posteriormente otimizados at? uma estrutura de menor energia
potencial e ?ngulos diedros adequados. No caso, tr?s processos de otimiza??o geom?trica, baseados
subsequentemente na teoria cl?ssica newtoniana, na semi-emp?rica e na teoria do funcional da
densidade (DFT), varreram a paisagem de energia de cada dipept?deos na busca de uma estrutura de
energia m?nima ideal. Por fim, os conf?rmeros ?timos foram descritos quanto ao potencial
eletrost?tico, energia de ioniza??o (amino?cidos), orbitais de fronteira HOMO/HOMO-1 e termo de
hopping. A partir dos termos de hopping descritos nesse trabalho, foi poss?vel, em estudos
subsequentes, caracterizar as propriedades de transporte de cargas destes modelos pept?dicos.
Vislumbra-se uma nova tecnologia de biosensores capaz de diagnosticar doen?as amiloides,
relacionadas ao ac?mulo de pept?deos disformes, a partir do perfil de condutividade el?trica
apresentado pelas prote?nas do paciente. Em um segundo momento dessa disserta??o, realiza-se um
estudo qu?ntico por modelagem molecular da energia de intera??o de um antibi?tico
aminoglicos?dico em seu receptor riboss?mico. Sabe-se que a higromicina B (higB) ? um antibi?tico
aminoglicos?deo que afeta a transloca??o ribossomal pela intera??o direta com a subunidade menor
do ribossomo bacteriano (30S), especificamente com nucleot?deos da h?lice 44 do RNA riboss?mico
16S (rRNA 16S). Devido ao forte car?ter eletrost?tico desta conex?o, foi proposta a investiga??o
energ?tica do mecanismo de liga??o da higB no 30S usando diferentes valores de constantes
diel?tricas (ε=0, 4, 10, 20 e 40), as quais s?o amplamente utilizadas no estudo das propriedades
eletrost?ticas de biomol?culas. Para isso, foram medidos raios crescentes centralizados no centr?ide
da higB tendo por base a estrutura cristalina higB-30S (1HNZ.pdb), e apenas a energia de intera??o
individual de cada nucleot?deo englobado foi calculada quanticamente utilizando a estrat?gia de
fracionamento molecular com capuzes conjugados (MFCC). Percebeu-se que as constantes
diel?tricas subestimam as energias de intera??o individuais, permitindo que o estado de
converg?ncia energ?tica seja alcan?ado rapidamente. Por?m apenas para ε=40, a energia de
intera??o total droga-receptor se estabilizou em r=18?, o que se constituiu como um adequado s?tio
de liga??o, pois englobou os res?duos do 16S que interagem mais fortemente com a higB - C1403,
C1404, G1405, A1493, G1494, U1495, C1496 e U1498. Assim, a constante diel?trica ≈40 ? ideal para
o tratamento de sistemas com muitas cargas. Confrontando as energias de liga??o individuais dos
nucleot?deos 16SrRNA com ensaios experimentais para determina??o da concentra??o inibit?ria
m?nima (MIC) da higB, acredita-se que esses res?duos com elevados valores de intera??o gerariam
resist?ncia bacteriana ? droga quando mutados. Com o mesmo racioc?nio, visto que aqueles com
baixa energia n?o influenciariam de forma eficaz a afinidade da higB em seu s?tio de liga??o, n?o
ocorreria perda de efic?cia caso fossem substitu?dos.
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