Spectrally Resolved Estimation of Water Entropy in the Active Site of Human Carbonic Anhydrase II.

A major challenge in understanding ligand binding to biomacromolecules lies in dissecting the underlying thermodynamic driving forces at the atomic level. Quantifying the contributions of water molecules is often especially demanding, although they can play important roles in biomolecular recognition and binding processes. One example is human carbonic anhydrase II, whose active site harbors a conserved network of structural water molecules that are essential for enzymatic catalysis.

Estimation of Protein-Ligand Unbinding Kinetics Using Non-Equilibrium Targeted Molecular Dynamics Simulations.

We here report on nonequilibrium targeted molecular dynamics simulations as a tool for the estimation of protein-ligand unbinding kinetics. Correlating simulations with experimental data from SPR kinetics measurements and X-ray crystallography on two small molecule compound libraries bound to the N-terminal domain of the chaperone Hsp90, we show that the mean nonequilibrium work computed in an ensemble of trajectories of enforced ligand unbinding is a promising predictor for ligand unbinding rates. We furthermore investigate the molecular basis determining unbinding rates within the compound libraries.

Monitoring transient events in infrared spectra using local mode analysis.

Time-resolved Fourier transformed infrared (FTIR) spectroscopy of chemical reactions is highly sensitive to minimal spatiotemporal changes. Structural features are decoded and represented in a comprehensible manner by combining FTIR spectroscopy with biomolecular simulations. Local mode analysis (LMA) is a tool to connect molecular motion based on a quantum mechanics simulation with infrared (IR) spectral features and vice versa.

The Second Law of Thermodynamics as a Force Law.

The second law of thermodynamics states the increase of entropy, Δ S > 0 , for real processes from state A to state B at constant energy from chemistry over biological life and engines to cosmic events. The connection of entropy to information, phase-space, and heat is helpful but does not immediately convince observers of the validity and basis of the second law. This gave grounds for finding a rigorous, but more easily acceptable reformulation.

Local Mode Analysis: Decoding IR Spectra by Visualizing Molecular Details.

Integration of experimental and computational approaches to investigate chemical reactions in proteins has proven to be very successful. Experimentally, time-resolved FTIR difference-spectroscopy monitors chemical reactions at atomic detail. To decode detailed structural information encoded in IR spectra, QM/MM calculations are performed.