Applications of metadynamics to protein-ligand docking

In the lecture, applications of enhanced sampling approaches (e.g., metadynamics) to study protein-drug interactions were illustrated

Reconstructing the free energy landscape of E-Cadherin conformational transition by metadynamics simulations

In classical cadherins, the mechanism by which three dimensional (3D) domain swapping leads to protein dimerization is still debated[1]. According to the 3D swapping model, two cadherin monomers mutually exchange a small portion of their N-terminal extracellular domain and form a homodimer. Two possible dimerization pathways have been proposed: a selected fit mechanism, based on the hypothesis that only monomers in an active conformational state can bind, and the induced fit mechanism, which requires the formation of an intermediate complex preceding the dimerization. Exploiting the advantages of metadynamics simulations in sampling protein conformational changes, the selected fit mechanism has been tested by reconstructing the free energy profile of E-cadherin monomer conformational change, leading to the active form. Calculations have also showed that the E-cadherin free state conformational equilibrium is strongly affected by the presence of calcium ions, which behave as allosteric activators in the opening process. We acknowledge HPC-Europa2 Programme (Application number 1024) and the Ministero dell'Universit\ue0 e della Ricerca (bando FIRB 2008 RBFR088ITV) for financial support

The role of the peripheral anionic site and cation-pi interactions in the ligand penetration of the human AChE gorge.

We study the ligand (tetramethylammonium) recognition by the peripheral anionic site and its penetration of the human AChE gorge by using atomistic molecular dynamics simulations and our recently developed metadynamics method. The role of both the peripheral anionic site and the formation of cation-pi interactions in the ligand entrance are clearly shown. In particular, a simulation with the W286A mutant shows the fundamental role of this residue in anchoring the ligand at the peripheral anionic site of the enzyme and in positioning it prior to the gorge entrance. Once the ligand is properly oriented, the formation of specific and synchronized cation-pi interactions with W86, F295, and Y341 enables the gorge penetration. Eventually, the ligand is stabilized in a free energy basin by means of cation-pi interactions with W86

Investigating biological systems with first principles Car-Parrinello molecular dynamics simulations

Density functional theory (DFT)-based Car–Parrinello molecular dynamics (CPMD) simulations describe the time evolution of molecular systems without resorting to a predefined potential energy surface. CPMD and hybrid molecular mechanics/CPMD schemes have recently enabled the calculation of redox properties of electron transfer proteins in their complex biological environment. They provided structural and spectroscopic information on novel platinum-based anticancer drugs that target DNA, also setting the basis for the construction of force fields for the metal lesion. Molecular mechanics/CPMD also lead to mechanistic hypotheses for a variety of metalloenzymes. Recent advances that increase the accuracy of DFT and the efficiency of investigating rare events are further expanding the domain of CPMD applications to biomolecules

Assessing the accuracy of metadynamics

Metadynamics is a powerful technique that has been successfully exploited to explore the multidimensional free energy surface of complex polyatomic systems and predict transition mechanisms in very different fields, ranging from chemistry and solid-state physics to biophysics. We here derive an explicit expression for the accuracy of the methodology and provide a way to choose the parameters of the method in order to optimize its performance