Multiscale simulation of fluid flow interaction with biological macromolecules

Papež, Petra (author), Praprotnik, Matej (mentor), Merzel, Franci (comentor)

Proteins are natural polymers that play an essential role both in living organisms and in biotechnological applications. While most of the protein's function evolves in the thermodynamic equilibrium, proteins can also be exposed to non-equilibrium states generated by mechanical stress that can impair their structure. As the structure of protein molecules is critically related to their function, any excessive structural change can lead to a reduced activity or a complete loss of it. For this reason, it is necessary to understand and determine the susceptibility of these biomolecules to mechanical stress, and the key to this knowledge is usually hidden in their dynamic response. In this thesis, we establish a methodology and an analytical framework that allow us to study the effects of acoustic excitations and hydrodynamic shear flow on the internal, rotational, and conformational dynamics of biological macromolecules. To capture the details of this interaction, we need to allow the molecular system to exchange mass and momentum with its surroundings. This is possible with the open-boundary molecular dynamics (OBMD) method, which enables grand-canonical simulations in and out of equilibrium. In OBMD simulations, the external boundary conditions are imposed on the system by an additional external force without modifying Newton's equations of motion in the bulk. We extend the OBMD method to simulate the propagation of acoustic waves in liquid water described by the mesoscopic dissipative particle dynamics (DPD) and simple point-charge (SPC) water models. Evaluating density variation for sound waves of different frequencies in the terahertz (THz) range, we show that our particle-based methodology can recover the fluctuating hydrodynamic description of acoustic waves in the continuum limit. Furthermore, we apply the developed methodology to excite low-frequency vibrational motions in the protein. To this end, we show that the sub-THz acoustic excitations enhance the protein's internal dynamics. On the other hand, by subjecting the protein to a shear flow of various strengths, we demonstrate that extraordinarily high shear rates must be applied to observe unfolding, the extent of which depends on the applied shear rate. Furthermore, we show that the protein gains vibrational angular momentum at higher shear rates, which is reflected in higher angular velocity and confirmed by analyzing the contributions to the total kinetic energy of the biomolecule.

• Language: English
• Keywords: biological macromolecules, dissipative particle dynamics, open-boundary molecular dynamics, sound wave, principal component analysis, shear flow, Eckart frame formalism, vibration and rotation
• Work type: Doctoral dissertation
• Typology: 2.08 - Doctoral Dissertation
• Organization: FMF - Faculty of Mathematics and Physics
• Year: 2024
• PID: 20.500.12556/RUL-158660
• COBISS.SI-ID: 199420675
• Publication date in RUL: 19.06.2024

Secondary language

• Language: Slovenian
• Title: Večskalne simulacije interakcije tekočinskega toka z biološkimi makromolekulami

Abstract

Proteini so naravni polimeri, ki v živih organizmih opravljajo mnoge za življenje pomembne funkcije. Čeprav svojo funkcijo največkrat opravljajo v termodinamskem ravnovesju, so lahko izpostavljeni tudi mnogim neravnovesnim pogojem, ki nastanejo kot posledica mehanskih napetosti. Slednje lahko poškodujejo proteinsko strukturo in povzročijo zmanjšanje ali celo popolno izgubo njihove funkcije. Zaradi tega je potrebno razumeti in določiti občutljivost teh biomolekul na mehanske napetosti, pri čemer se ključ do tega znanja običajno skriva v njihovem dinamičnem odzivu. V doktorskem delu vzpostavimo metodologijo in analitični pristop, ki nam omogočata preučevanje vpliva akustičnih vzbujanj in hidrodinamskega strižnega toka na interno, rotacijsko in konformacijsko dinamiko bioloških makromolekul. Za opis interakcije tekočinskega toka z biomolekulami, pa moramo sistemu omogočiti, da z okolico izmenjuje snov, gibalno količino in energijo. Primerno simulacijsko tehniko predstavlja odprta simulacija molekulske dinamike [ang. open-boundary molecular dynamics (OBMD)], saj omogoča ravnovesne in neravnovesne simulacije sistema v velekanoničnem ansamblu. V simulacijah OBMD zunanje robne pogoje vpeljemo preko dodatne zunanje sile. V doktorskem delu metodo OBMD razširimo tako, da omogoča simulacije širjenja zvočnih valov v tekoči vodi, ki jo opišemo z mezoskopskim modelom disipativne delčne dinamike [ang. dissipative particle dynamics (DPD)]. Z izračunom časovnega poteka gostotnih variacij zvočnih valov v teraherčnem (THz) frekvenčnem območju pokažemo, da je naša metodologija zmožna opisati širjenje zvoka na kontinuumski skali. Razvito metodologijo uporabimo tudi za vzbujanje nizkofrekvenčnih normalnih načinov nihanja proteina in ugotovimo, da vzbujanje z akustičnimi valovi ustrezne frekvence vzbudi njegovo interno dinamiko. Poleg tega protein izpostavimo še strižnemu toku različnih jakosti in raziščemo njegovo rotacijsko in konformacijsko dinamiko. Prikažemo, da se protein v strižnem toku zvija in razvija, pri čemer je obseg razvitja odvisen od jakosti strižnega toka. Izračunamo tudi, da se sučni del vibracijskega prispevka pri višjih strižnih hitrostih poveča, kar se odraža tudi v večji kotni hitrosti biomolekule in kar potrdimo z analizo prispevkov translacijske, rotacijske in vibracijske energije k skupni kinetični energiji biomolekule.

• Keywords: biološke makromolekule, disipativna delčna dinamika, odprta simulacija molekulske dinamike, zvočni val, metoda glavnih osi, strižni tok, Eckartov sistem, vibracije in rotacije