Simulacije molekulske dinamike proteina MntR iz bakterije Mycobacterium tuberculosis

master's thesis

• Title (english): Molecular dynamics simulations of the MntR protein from the bacterium Mycobacterium tuberculosis
• Author: Mislav Brajković
• Mentor: Branimir Bertoša (mentor)
• Committee member: Branimir Bertoša (predsjednik povjerenstva)
• Committee member: Ivana Ivančić Baće (član povjerenstva)
• Committee member: Martina Šeruga Musić (član povjerenstva)
• Committee member: Davor Kovačević (član povjerenstva)
• Granter: University of Zagreb; Faculty of Science; (Department of Biology); Zagreb
• Defense date and country: 2022-01-27, Croatia
• Scientific / art field, discipline and subdiscipline: NATURAL SCIENCES; Biology

Abstract

Homodimerni protein MntR (engl. Manganese Transport Regulator) regulira unutarstaničnu
koncentraciju Mn2+ iona u bakteriji Mycobacterium tuberculosis represijom gena za njihov unos. Ovaj
protein stvara interakcije s DNA u holo formi (s vezanim manganom), a u apo formi (bez vezanog
mangana) je neaktivan. Molekularni mehanizam aktivacije proteina za vezanje DNA nije u potpunosti
razjašnjen. Kako bi se istražile razlike strukturnih i dinamičkih svojstava apo i holo strukture proteina,
provedene su računalne simulacije molekulske dinamike (MD). Analizom MD simulacija ustanovljeno
je da su DNA-vezujuće domene (domene HTH) i N-terminalni lanci proteina MntR međusobno bliže u
simulacijama holo strukture u usporedbi s apo strukturom. Približavanje domena HTH mogući je
mehanizam aktivacije proteina za vezanje molekule DNA, ali potrebne su dodatne simulacije i
eksperimenti kako bi to potvrdili. Manganovi ioni uzrokovali su i smanjenje fleksibilnosti nekih αzavojnica tijekom MD simulacija ukazujući na još jednu razliku apo i holo forme. Pronađena je mreža
nekovalentnih interakcija između domena HTH i FeoA. Rezultati MD simulacija pokazuju da je ta
mreža interakcija neophodna u povezivanju domena HTH i FeoA, prekidanje te mreže interakcija
dovodi do odvajanja tih domena. Također, prekid te mreže interakcija uzrokuje i približavanje domena
HTH među podjedinicama proteina što moguće ima utjecaj sposobnost vezanja DNA.

Abstract (english)

MntR (Manganese Transport Regulator) is a homodimeric protein that regulates intracellular
manganese ion concentration in the bacterium Mycobacterium tuberculosis by repressing the Mn2+
intake genes. As contrast to the inactive apo structure (without bound manganese ions), the holo
structure (with bound manganese ions) of MntR can form interactions with DNA. The molecular
mechanism by which MntR is activated for DNA binding is unknown. Molecular dynamics (MD)
simulations were performed to compare structural and dynamical properties of apo and holo MntR
structures. MD simulations revealed that DNA-binding domains (HTH domains) and N-terminal
chains were closer in simulations of holo structure than in apo structure. This might improve DNA
binding and could represent a mechanism of MntR activation. However, this hypothesis needs to be
confirmed by additional MD simulations and experiments. Another distinction between apo and holo
structures is that Mn2+ in holo structures causes a decrease of the flexibility of some α-helices.
Analyses of MD simulations identified network of non-covalent interactions between the HTH and
FeoA domains. Disruption of this network caused the HTH and FeoA domains to separate, proving its
critical role in inter-domain communication. In addition, breaking of the interdomain interaction
network also brought the HTH domains close together, which may have an impact on DNA binding.

• Keywords: protein MntR; homeostaza mangana; molekulska dinamika; alosterička aktivacija; metaloregulatorni proteini
• Keywords (english): MntR protein; manganese homeostasis; molecular dynamics; alosteric activation; metalloregulatory proteins
• Language: croatian
• URN:NBN: urn:nbn:hr:217:005298
• Study programme: Title: Molecular Biology; Study programme type: university; Study level: graduate; Academic / professional title: magistar/magistra molekularne biologije (magistar/magistra molekularne biologije)
• Type of resource: Text
• File origin: Born digital
• Access conditions: Open access
• Created on: 2022-01-31 13:26:48