Design of new protocols to improve the efficiency of Markov State Model construction - Application to a human synaptic receptor

Van Elteren, Jan (author), Reščič, Jurij (mentor), Cecchini, Marco (comentor)

This Master’s thesis describes two novel protocols developed to lower the cost of Markov state model construction for the glycine receptor: i) transition path sampling; and ii) the perturbative approach. Coarse-grained transition path sampling with eBDIMS, combined with atomistic detail reconstruction using cg2all reproduced biologically relevant low-energy intermediate structures between preexisting end-state structures. On the other hand, perturbative ligand morphing and ligand insertion were utilized for the creation of new structures based on knowledge about related systems. Maximum common substructure alignment (MCS) proved useful for ligand morphing, while a primitive alignment approach outperformed docking for the insertion of ligands. The newly developed methods were applied to the agonist-bound glycine receptor. Notably, perturbative ligand insertion showed promise in significantly reducing the computational cost of sampling the entire conformational ensemble that is needed for the subsequent creation of a Markov state model of the biological system.

• Language: English
• Keywords: Markov state modelling, molecular dynamics, glycine receptor
• Work type: Master's thesis/paper
• Typology: 2.09 - Master's Thesis
• Organization: FKKT - Faculty of Chemistry and Chemical Technology
• Year: 2024
• PID: 20.500.12556/RUL-161045
• COBISS.SI-ID: 214837251
• Publication date in RUL: 06.09.2024

Secondary language

• Language: Slovenian
• Title: Oblikovanje novih postopkov za izboljšanje učinkovitosti Markovega modela stanj; aplikacija na človeškem sinaptičnem receptorju

Abstract

V magistrski nalogi sta bila razvita dva nova postopka za znižanje računalniške cene konstrukcije Markovega modela stanj za glicinski receptor: i) vzorčenje prehodne poti in ii) perturbativni pristop. Kombinacija vzorčenja grobozrnate prehodne poti z eBDIMS in rekonstrukcija atomističnih podrobnosti s cg2all je reproducirala biološko relevantne nizkoenergijske strukture med obstoječimi končnimi strukturami. Perturbativna pristopa preobrazbe ligandov in vstavljanja ligandov sta bila uporabljena za ustvarjanje novih struktur na podlagi znanja o sorodnih sistemih. Poravnava največje skupne podstrukture (MCS) se je izkazala za uporabno pri preobrazbi ligandov, medtem ko je bila poravnava struktur bolj učinkovita za vstavljanje ligandov kot molekulsko umeščanje. Razviti postopki so bili uporabljeni na glicinskem receptorju, na katerega je vezan agonist. Zlasti perturbativna vstavitev ligandov se je izkazala za obetavno pri vzorčenju celotnega konformacijskega ansambla, ki je potreben za nadaljnjo izdelavo Markovega modela stanj biološkega sistema.

• Keywords: Markovo modeliranje stanj, molekulska dinamika, glicinski receptor