Force Field Optimization Guided by Small Molecule Crystal Lattice Data Enables Consistent Sub-Angstrom Protein–Ligand Docking

AutoDock4Zn: An Improved AutoDock Force Field for Small-Molecule Docking to Zinc Metalloproteins

Zinc is present in a wide variety of proteins and is important in the metabolism of most organisms. Zinc metalloenzymes are therapeutically relevant targets in diseases such as cancer, heart disease, bacterial infection, and Alzheimer's disease. In most cases a drug molecule targeting such enzymes establishes an interaction that coordinates with the zinc ion. Thus, accurate prediction of the in...

Structure-guided optimization of small molecule c-Abl activators

c-Abl kinase is maintained in its normal inactive state in the cell through an assembled, compact conformation. We describe two chemical series that bind to the myristoyl site of the c-Abl kinase domain and stimulate c-Abl activation. We hypothesize that these molecules activate c-Abl either by blocking the C-terminal helix from adopting a bent conformation that is critical for the formation of...

Sub-angstrom conformational changes of a single molecule captured by AFM variance analysis.

A system's equilibrium variance can be analyzed to probe its underlying dynamics at higher resolution. Here, using single-molecule atomic-force microscope techniques, we show how the variance in the length of a single dextran molecule can be used to establish thermodynamic equilibrium and to detect conformational changes not directly observable with other methods. Dextran is comprised of a chai...

Direct Imaging of Water/Lipid Interface by Frequency Modulation Atomic Force Microscopy at Sub-Angstrom Resolution

Frequency modulation atomic force microscopy (FM-AFM) has been used in ultra high vacuum (UHV) environments for investigating subnanometer-scale structures and functions of various surfaces. Until recently, however, its operating environment had been limited only to UHV, which has prevented its practical applications in air and liquids. Recently, Fukuma et al. presented a way to overcome this l...

Crystal Lattice Imaging Using Atomic Force Microscopy