Biology subjects

Romany, A.

Publications and source records attributed to Romany, A..

3 recordsLinked to original sources

bioRxiv2025

Electric Field Induces Dewetting Transitions in Amphiphilic Crystalline Domains of Chitosan-Based Hydrogels

Electrofabrication has emerged as a versatile technique for creating complex functional materials from self-assembling biopolymers such as chitosan and collagen; however, a molecular-level understanding of electric cueing remains lacking. Here we investigate how a mild electric field (similar in magnitude to that imposed on biological membranes) remodels the nanofibril structure of chitosan hydrogels using all-atom molecular dynamics simulations. The simulations revealed a mechanism of active dewetting, in which the electric field enhances fibrillar order and induces compaction along the sheet-stacking direction through expulsion of water and stabilization of the hydrogen-bond network within and between fibril sheets. This mechanism provides a physical basis for a recent experimental observation that electrodeposited chitosan hydrogel film undergoes vertical contraction. The electric field-induced dewetting between amphiphilic chitosan sheets is reminiscent of but fundamentally different from the classic dewetting phenomenon for purely hydrophobic systems, which has been intensively studied by both theoretical and experimental communities in the past. Using active dewetting to control microstructures has implications for tailored engineering of functional materials such as artificial bones and tissues based on self-assembling chitosan. TOC Graphic O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=111 SRC="FIGDIR/small/650622v4_ufig1.gif" ALT="Figure 1"> View larger version (29K): org.highwire.dtl.DTLVardef@fc99e9org.highwire.dtl.DTLVardef@1dccbfforg.highwire.dtl.DTLVardef@d50dc6org.highwire.dtl.DTLVardef@17b550e_HPS_FORMAT_FIGEXP M_FIG C_FIG

biophysics↗

bioRxiv2023

Mechanism of Dimer Selectivity and Binding Cooperativity of BRAF inhibitors

Aberrant signaling of BRAFV600E is a major cancer driver. Current FDA-approved RAF inhibitors selectively inhibit the monomeric BRAFV600E and suffer from tumor resistance. Recently, dimer-selective and equipotent RAF inhibitors have been developed; however, the mechanism of dimer selectivity is poorly understood. Here, we report extensive molecular dynamics (MD) simulations of the monomeric and dimeric BRAFV600E in the apo form or in complex with one or two dimer-selective (PHI1) or equipotent (LY3009120) inhibitor(s). The simulations uncovered the unprecedented details of the remarkable allostery in BRAFV600E dimerization and inhibitor binding. Specifically, dimerization retrains and shifts the C helix inward and increases the flexibility of the DFG motif; dimer compatibility is due to the promotion of the C-in conformation, which is stabilized by a hydrogen bond formation between the inhibitor and the C Glu501. A more stable hydrogen bond further restrains and shifts the C helix inward, which incurs a larger entropic penalty that disfavors monomer binding. This mechanism led us to propose an empirical way based on the co-crystal structure to assess the dimer selectivity of a BRAFV600E inhibitor. Simulations also revealed that the positive cooperativity of PHI1 is due to its ability to preorganize the C and DFG conformation in the opposite protomer, priming it for binding the second inhibitor. The atomically detailed view of the interplay between BRAF dimerization and inhibitor allostery as well as cooperativity has implications for understanding kinase signaling and contributes to the design of protomer selective RAF inhibitors.

biophysics↗

bioRxiv2023

Mechanism of the Temperature-Dependent Self-Assembly and Polymorphism of Chitin

Chitin is the second most abundant natural biopolymer; its crystalline structures have been extensively studied; however, the mechanism of chitins self-assembly is unknown. Here we applied all-atom molecular dynamics to study chitins self-assembly process at different temperatures. Strikingly, at 278 K, an amorphous aggregate was formed, whereas at 300 K single-sheet and at 323 K both single- and multi-sheet nanofibril regions were formed. The nanofibrils contain antiparallel, parallel or mixed orientation chains, with antiparallel being slightly preferred, recapitulating chitins polymorphism observed in nature. The inverse temperature dependence is consistent with the recent experiment. The analysis suggested that the multi-sheet nanofibrils are assembled by stacking the single nanofibril sheets, which are formed through two types of pathways in which hydrophobic collapse either precedes or is concomitant with increasing number of interchain hydrogen bonds and solvent expulsion. Furthermore, the antiparallel and parallel chains are mediated by different interchain hydrogen bonds. The analysis also suggested that the inverse temperature dependence may be attributed to the hydrophobic effect reminiscent of the low critical solution temperature phase behavior. The present study provides a rich, atomic-level view of chitins polymorphic self-assembly process, paving the way for the rational design of chitin-derived novel materials.

bioengineering↗