0000000000226127
AUTHOR
Noora Aho
Best Practices in Constant pH MD Simulations: Accuracy and Sampling
Various approaches have been proposed to include the effect of pH in molecular dynamics (MD) simulations. Among these, the λ-dynamics approach proposed by Brooks and co-workers [Kong, X.; Brooks III, C. L. J. Chem. Phys.1996, 105, 2414−2423] can be performed with little computational overhead and hfor each typeence be used to routinely perform MD simulations at microsecond time scales, as shown in the accompanying paper [Aho, N. et al. J. Chem. Theory Comput.2022, DOI: 10.1021/acs.jctc.2c00516]. At such time scales, however, the accuracy of the molecular mechanics force field and the parametrization becomes critical. Here, we address these issues and provide the community with guidelines on…
Scalable Constant pH Molecular Dynamics in GROMACS
Molecular dynamics (MD) computer simulations are used routinely to compute atomistic trajectories of complex systems. Systems are simulated in various ensembles, depending on the experimental conditions one aims to mimic. While constant energy, temperature, volume, and pressure are rather straightforward to model, pH, which is an equally important parameter in experiments, is more difficult to account for in simulations. Although a constant pH algorithm based on the λ-dynamics approach by Brooks and co-workers [Kong, X.; Brooks III, C. L. J. Chem. Phys.1996, 105, 2414–2423] was implemented in a fork of the GROMACS molecular dynamics program, uptake has been rather limited, presumably due to…
Exploring fast proton transfer events associated with lateral proton diffusion on the surface of membranes
Proton diffusion (PD) across biological membranes is a fundamental process in many biological systems, and much experimental and theoretical effort has been employed for deciphering it. Here, we report on a spectroscopic probe, which can be tightly tethered to the membrane, for following fast (nanosecond) proton transfer events on the surface of membranes. Our probe is composed of a photoacid that serves as our light-induced proton source for the initiation of the PD process. We use our probe to follow PD, and its pH dependence, on the surface of lipid vesicles composed of a zwitterionic headgroup, a negative headgroup, a headgroup that is composed only from the negative phosphate group, or…
A spontaneous mitonuclear epistasis converging on Rieske Fe-S protein exacerbates complex III deficiency in mice
We previously observed an unexpected fivefold (35 vs. 200 days) difference in the survival of respiratory chain complex III (CIII) deficient Bcs1lp.S78G mice between two congenic backgrounds. Here, we identify a spontaneous homoplasmic mtDNA variant (m.G14904A, mt-Cybp.D254N), affecting the CIII subunit cytochrome b (MT-CYB), in the background with short survival. We utilize maternal inheritance of mtDNA to confirm this as the causative variant and show that it further decreases the low CIII activity in Bcs1lp.S78G tissues to below survival threshold by 35 days of age. Molecular dynamics simulations predict D254N to restrict the flexibility of MT-CYB ef loop, potentially affecting RISP dyna…
Molecular dynamics simulations of acids and bases in biomolecular environments
Useiden biologisten kokonaisuuksien, kuten entsyymien tai solukalvojen, toimintaan vaikuttaa niitä ympäröivän liuoksen happamuus, jota kuvataan yleisesti pH-arvolla. Paikallinen pH vaikuttaa atomitasolla biomolekyylien kemiallisten ryhmien protonaatioasteeseen eli siihen, onko kyseisiin ryhmiin sitoutunut protoni. Protonien sitoutuminen muuttaa molekyylien varauksia, jolloin niiden ja ympäristön välisten sähköisten vuorovaikutusten suuruus voi muuttua. Tällä on vaikutus biomolekyylien rakenteeseen ja niiden ominaisuuksiin, vaikuttaen lopulta koko biologisen kokonaisuuden toimintaan. Kokeellisen tutkimuksen lisäksi biomolekyylien toimintaa atomitasolla voidaan tutkia laskennallisesti moderni…