A novel and robust automated docking method that predicts the bound conformations of flexible ligands to macromolecular targets has been developed and tested, in combination with a new scoring function that estimates the free energy change upon binding. Interestingly, this method applies a Lamarckian model of genetics, in which environmental adaptations of an individual's phenotype are reverse transcribed into its genotype and become . heritable traits sic . We consider three search methods, Monte Carlo simulated annealing, a traditional genetic algorithm, and the Lamarckian genetic algorithm, and compare their performance in dockings of seven protein)ligand test systems having known three-dimensional structure. We show that both the traditional and Lamarckian genetic algorithms can handle ligands with more degrees of freedom than the simulated annealing method used in earlier versions of AUTODOCK, and that the Lamarckian genetic algorithm is the most efficient, reliable, and successful of the three. The empirical free energy function was calibrated using a set of 30 structurally known protein)ligand complexes with experimentally determined binding constants. Linear regression analysis of the observed binding constants in terms of a wide variety of structure-derived molecular properties was performed. The final model had a residual standard y1 y1 .

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Automated docking using a Lamarckian genetic algorithm and an empirical binding free energy function

http://experimentationlab.berkeley.edu/sites/default/files/AFMImages/butt_AFM.pdf

Force measurements with the atomic force microscope: Technique, interpretation and applications

Dynamic strength of molecular adhesion bonds.

Atomic force microscopy (AFM) has been used to measure the strength of bonds between biological receptor molecules and their ligands. But for weak noncovalent bonds, a dynamic spectrum of bond strengths is predicted as the loading rate is altered, with the measured strength being governed by the prominent barriers traversed in the energy landscape along the force-driven bond-dissociation pathway. In other words, the pioneering early AFM measurements represent only a single point in a continuous spectrum of bond strengths, because theory predicts that these will depend on the rate at which the load is applied. Here we report the strength spectra for the bonds between streptavidin (or avidin) and biotins-the prototype of receptor-ligand interactions used in earlier AFM studies, and which have been modelled by molecular dynamics. We have probed bond formation over six orders of magnitude in loading rate, and find that the bond survival time diminished from about 1 min to 0.001 s with increasing loading rate over this range. The bond strength, meanwhile, increased from about 5 pN to 170 pN. Thus, although they are among the strongest noncovalent linkages in biology (affinity of 10(13) to 10(15) M(-1)), these bonds in fact appear strong or weak depending on how fast they are loaded. We are also able to relate the activation barriers derived from our strength spectra to the shape of the energy landscape derived from simulations of the biotin-avidin complex.

Energy landscapes of receptor–ligand bonds explored with dynamic force spectroscopy

http://kbose.weebly.com/uploads/1/0/4/9/10492046/force-distance_curves_by_atomic_force_microscopy_1.pdf

Force-distance curves by atomic force microscopy

The recognition mechanisms and dissociation pathways of the avidin-biotin complex and of actin monomers in actin filaments were investigated. The unbinding forces of discrete complexes of avidin or streptavidin with biotin analogs are proportional to the enthalpy change of the complex formation but independent of changes in the free energy. This result indicates that the unbinding process is adiabatic and that entropic changes occur after unbinding. On the basis of the measured forces and binding energies, an effective rupture length of 9.5 +/- 1 angstroms was calculated for all biotin-avidin pairs and approximately 1 to 3 angstroms for the actin monomer-monomer interaction. A model for the correlation among binding forces, intermolecular potential, and molecular function is proposed.

https://science.sciencemag.org/content/sci/266/5183/257.full.pdf

Vincent T. Moy

Papers

Intermolecular forces and energies between ligands and receptors

Sensing specific molecular interactions with the atomic force microscope

Shapes of finite two-dimensional lipid domains

Long-range molecular orientational order in monolayer solid domains of phospholipid

Theory of superstructures in lipid monolayer phase transitions