Abstract. In structured RNAs, helical elements are often capped by apical loops that are integral structural elements, ranging from 3 to >20 nts of size

MolAR is the first memory-safe library for analysis of MD simulations written in Rust. MolAR is intended to explore the advantages and challenges of implementing molecular analysis software in the me...

Proinsulin folding requires dynamic positioning of the C-peptide to guide A- and B-chain alignment and disulfide pairing. Mutant INS-gene-induced diabetes of youth (MIDY) arises when single-residue substitutions disrupt this process. We mapped the conformational free-energy landscapes of wild-type (WT) proinsulin and seven MIDY variants using metadynamics and molecular dynamics simulations. WT exhibits a deep free-energy minimum at compact conformations. In contrast, MIDY mutants display a continuum of destabilization: E(A4)K retains near-WT stability, Akita (C(A7)Y), V(B18)A, and R(Cpep + 2)C show moderate loss of the native basin, while H(B5)D, L(A16)P, and Y(B26)C collapse the closed–open barrier and populate misfolded open states >50% of the time. Structural analyses reveal that WT and E(A4)K preserve robust A–C docking, with the C-peptide flexibly engaging the A-chain groove. Destabilizing mutants progressively erode these native A–C contacts while forming compensatory, non-native B–C interactions. Per-residue energy decomposition highlights the loss of canonical salt bridges and emergence of aberrant electrostatic and hydrophobic hot spots, correlating with the collapse of the folding free-energy barrier. Secondary-structure analysis further shows that mutants rigidify the normally disordered C-peptide, increasing helical or strand propensity in a mutation-specific manner. Collectively, these findings establish a continuum from near-native stability to overt misfolding, mechanistically linking single-site mutations to altered folding landscapes and aggregation risk in MIDY. The results highlight the C-peptide as a dynamic linchpin of proinsulin folding and suggest that restoring its flexible docking could provide a therapeutic avenue.

EmrE is a small multidrug resistance (SMR) pump of antiparallel topology that confers resistance to a broad range of polyaromatic cations in Escherichia coli. Atomic-level understanding of conforma...

Serum albumin (SA) is the most prevalent protein found in blood. Human albumin was used as an albumin substitute in hypoalbuminemia pets due to high sequence similarity. SAs from furry animals were...

The truncated Aβ1 − 16 peptide containing the metal-binding domain is frequently used in in silico and experimental investigations because it is more soluble and thus more suitable for studies in s...

The cytochrome bcc-aa3 supercomplex, a key component in the electron transport chain pathway involved in bacterial energy production and homeostasis, is a clinically validated target for tuberculos...

Ebola viral disease (EVD) is a highly infectious and potentially fatal illness with a case fatality rate ranging from 25% to 90%. To effectively control its spread, there is a need for rapid, relia...

Point mutation D54K in the human N-terminal caspase recruitment domain (CARD) of nucleotide-binding oligomerization domain −1 (NOD1) abrogates an imperative downstream interaction with receptor-int...

Ligand binding to G-quadruplex (G4) structures at human telomeric DNA ends promotes thermal stabilization, disrupting the interaction of the telomerase enzyme, which is found active in 80–85% of ca...

EmrE is a small multidrug resistance (SMR) pump of antiparallel topology that confers resistance to a broad range of polyaromatic cations in Escherichia coli. Atomic-level understanding of conforma...

Cellulases are enzymes that aid in the hydrolysis of cellulosic fibers and have a wide range of industrial uses. In the present in silico study, sequence alignment between cellulases from different...