Modeling of protein hydration dynamics is supported by THz spectroscopy of highly diluted solutions.

In this investigation, we report the effect on the microscopic dynamics and interactions of the cytokine interferon gamma (IFN-γ) and antibodies to IFN-γ (anti-IFN-γ) and to the interferon gamma receptor 1 (anti-IFNGR1) prepared in highly dilute (HD) solutions of initial proteins. THz spectroscopy measurements have been conducted as a means to analyze and characterize the collective dynamics of the HD samples. MD simulations have also been performed that have successfully reproduced the observed signatures from experimental measurement.

New insights into the microscopic interactions associated with the physical mechanism of action of highly diluted biologics.

In this investigation, we report the effect on the microscopic dynamics and interactions of the cytokine interferon gamma (IFN-γ) and antibodies to IFN-γ (anti-IFN-γ) and to the interferon gamma receptor 1 (anti-IFNGR1) prepared in exceptionally dilute solutions of initial proteins. Using both THz spectroscopy and molecular dynamics simulations we have uncovered that the high dilution method of sample preparation results in the reorganization of the sample surface residue dynamics at the solvent-protein interface that leads to both structural and kinetic heterogeneous dynamics that ultimately create interactions that enhance the binding probability of the antigen binding site. Our results indicate that the modified interfacial dynamics of anti-IFN-γ and anti-IFGNR1 that we probe experimentally are directly associated with alterations in the complementarity regions of the distinct antibodies that designate both antigen-antibody affinity and recognition.

Conformational perturbation, allosteric modulation of cellular signaling pathways, and disease in P23H rhodopsin.

In this investigation we use THz spectroscopy and MD simulation to study the functional dynamics and conformational stability of P23H rhodopsin. The P23H mutation of rod opsin is the most common cause of human binding autosomal dominant retinitis pigmentosa (ADRP), but the precise mechanism by which this mutation leads to photoreceptor cell degeneration has not yet been elucidated. Our measurements confirm conformational instability in the global modes of the receptor and an active-state that uncouples the torsional dynamics of the retinal with protein functional modes, indicating inefficient signaling in P23H and a drastically altered mechanism of activation when contrasted with the wild-type receptor.

Chlorophyll-Derivative Modulation of Rhodopsin Signaling Properties through Evolutionarily Conserved Interaction Pathways.

Retinal is the light-absorbing chromophore that is responsible for the activation of visual pigments and light-driven ion pumps. Evolutionary changes in the intermolecular interactions of the retinal with specific amino acids allow for adaptation of the spectral characteristics, referred to as spectral tuning. However, it has been proposed that a specific species of dragon fish has bypassed the adaptive evolutionary process of spectral tuning and replaced it with a single evolutionary event: photosensitization of rhodopsin by chlorophyll derivatives.

Vibrational resonance, allostery, and activation in rhodopsin-like G protein-coupled receptors.

G protein-coupled receptors are a large family of membrane proteins activated by a variety of structurally diverse ligands making them highly adaptable signaling molecules. Despite recent advances in the structural biology of this protein family, the mechanism by which ligands induce allosteric changes in protein structure and dynamics for its signaling function remains a mystery. Here, we propose the use of terahertz spectroscopy combined with molecular dynamics simulation and protein evolutionary network modeling to address the mechanism of activation by directly probing the concerted fluctuations of retinal ligand and transmembrane helices in rhodopsin.

Using THz Spectroscopy, Evolutionary Network Analysis Methods, and MD Simulation to Map the Evolution of Allosteric Communication Pathways in c-Type Lysozymes.

It is now widely accepted that protein function is intimately tied with the navigation of energy landscapes. In this framework, a protein sequence is not described by a distinct structure but rather by an ensemble of conformations. And it is through this ensemble that evolution is able to modify a protein's function by altering its landscape.

The glassy state of crambin and the THz time scale protein-solvent fluctuations possibly related to protein function.

Background: THz experiments have been used to characterize the picosecond time scale fluctuations taking place in the model, globular protein crambin.

Results: Using both hydration and temperature as an experimental parameter, we have identified collective fluctuations (<= 200 cm(-1)) in the protein. Observation of the protein dynamics in the THz spectrum from both below and above the glass transition temperature (Tg) has provided unique insight into the microscopic interactions and modes that permit the solvent to effectively couple to the protein thermal fluctuations.