PROTAC-induced Protein Structural Dynamics in Targeted Protein Degradation.

PROteolysis TArgeting Chimeras (PROTACs) are small molecules that induce target protein degradation via the ubiquitin-proteasome system. PROTACs recruit the target protein and E3 ligase; a critical first step is forming a ternary complex. However, while the formation a ternary complex is crucial, it may not always guarantee successful protein degradation.

Modeling receptor flexibility in the structure-based design of KRAS inhibitors.

KRAS has long been referred to as an 'undruggable' target due to its high affinity for its cognate ligands (GDP and GTP) and its lack of readily exploited allosteric binding pockets. Recent progress in the development of covalent inhibitors of KRAS has revealed that occupancy of an allosteric binding site located between the α3-helix and switch-II loop of KRAS-sometimes referred to as the 'switch-II pocket'-holds great potential in the design of direct inhibitors of KRAS. In studying diverse switch-II pocket binders during the development of sotorasib (AMG 510), the first FDA-approved inhibitor of KRAS, we found the dramatic conformational flexibility of the switch-II pocket posing significant challenges toward the structure-based design of inhibitors.

GeomBD3: Brownian Dynamics Simulation Software for Biological and Engineered Systems.

GeomBD3 is a robust Brownian dynamics simulation package designed to easily handle natural or engineered systems in diverse environments and arrangements. The software package described herein allows users to design, execute, and analyze BD simulations. The simulations use all-atom, rigid molecular models that diffuse according to overdamped Langevin dynamics and interact through electrostatic, Lennard-Jones, and ligand desolvation potentials.

Modeling structural interconversion in Alzheimers' amyloid beta peptide with classical and intrinsically disordered protein force fields.

A comprehensive understanding of the aggregation mechanism in amyloid beta 42 (Aβ42) peptide is imperative for developing therapeutic drugs to prevent or treat Alzheimer's disease. Because of the high flexibility and lack of native tertiary structures of Aβ42, molecular dynamics (MD) simulations may help elucidate the peptide's dynamics with atomic details and collectively improve ensembles not seen in experiments. We applied microsecond-timescale MD simulations to investigate the dynamics and conformational changes of Aβ42 by using a newly developed Amber force field ( We compared the and the regular force field by examining the conformational changes of two distinct Aβ42 monomers in explicit solvent.