Biology subjects

Mravic, M.

Publications and source records attributed to Mravic, M..

3 recordsLinked to original sources

bioRxiv2023

Ab initio prediction of specific phospholipid complexes and membrane association of HIV-1 MPER antibodies by multi-scale simulations

A potent class of HIV-1 broadly neutralizing antibodies (bnAbs) targets the envelope glycoproteins membrane proximal exposed region (MPER) through a proposed mechanism where hypervariable loops embed into lipid bilayers and engage headgroup moieties alongside the epitope. We address the feasibility and determinant molecular features of this mechanism using multi-scale modeling. All-atom simulations of 4E10, PGZL1, 10E8 and LN01 docked onto HIV-like membranes consistently form phospholipid complexes at key complementarity-determining region loop sites, solidifying that stable and specific lipid interactions anchor bnAbs to membrane surfaces. Ancillary protein-lipid contacts reveal surprising contributions from antibody framework regions. Coarse-grained simulations effectively capture antibodies embedding into membranes. Simulations estimating protein-membrane interaction strength for PGZL1 variants along an inferred maturation pathway show bilayer affinity is evolved and correlates with neutralization potency. The modeling demonstrated here uncovers insights into lipid participation in antibodies recognition of membrane proteins and highlights antibody features to prioritize in vaccine design.

biophysics↗

bioRxiv2023

Designed Transmembrane Proteins Inhibit the Erythropoietin Receptor in a Custom Binding Topology

Transmembrane (TM) domains as simple as a single span can perform complex biological functions using entirely lipid-embedded chemical features. Computational design has potential to generate custom tool molecules directly targeting membrane proteins at their functional TM regions. Thus far, designed TM domain-targeting agents have been limited to mimicking binding modes and motifs of natural TM interaction partners. Here, we demonstrate the design of de novo TM proteins targeting the erythropoietin receptor (EpoR) TM domain in a custom binding topology competitive with receptor homodimerization. The TM proteins expressed in mammalian cells complex with EpoR and inhibit erythropoietin-induced cell proliferation. In vitro, the synthetic TM domain complex outcompetes EpoR homodimerization. Structural characterization reveals that the complex involves the intended amino acids and agrees with our designed molecular model of antiparallel TM helices at 1:1 stoichiometry. Thus, membrane protein TM regions can now be targeted in custom designed topologies.

bioengineering↗

bioRxiv2022

Transient Water Wires Mediate Selective Proton Conduction in Designed Channel Proteins

Summary paragraphSelective proton transport through proteins is essential for forming and utilizing proton gradients in cells. Protons are conducted along hydrogen-bonded "wires" of water molecules and polar sidechains, which, somewhat surprisingly, are often interrupted by dry apolar stretches in the conduction pathways inferred from static protein structures. We hypothesize that protons are conducted through such dry spots by forming transient water wires, often highly correlated with the presence of the excess proton itself in the water wire. To test this hypothesis, we used molecular dynamics simulations to design transmembrane channels with stable water pockets interspersed by apolar segments capable of forming flickering water wires. The minimalist designed channels conduct protons at rates similar to viral proton channels, and they are at least 106-fold more selective for H+ over Na+. These studies inform mechanisms of biological proton conduction and principles for engineering proton-conductive materials.

biophysics↗