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We examine vibrational energy flow in dehydrated and hydrated villin headpiece subdomain HP36 by master equation simulations. Transition rates used in the simulations are obtained from communication maps calculated for HP36. In addition to energy flow along the main chain, we identify pathways for energy transport in HP36 via hydrogen bonding between residues quite far in sequence space. The results of the master equation simulations compare well with all-atom non-equilibrium simulations to about 1 ps following initial excitation of the protein, and quite well at long times, though for some residues we observe deviations between the master equation and all-atom simulations at intermediate times from about 1-10 ps. Those deviations are less noticeable for hydrated than dehydrated HP36 due to energy flow into the water. [ABSTRACT FROM AUTHOR]

Allostery represents a fundamental mechanism of biological regulation that is mediated via long-range communication between distant protein sites. Although little is known about the underlying dynamical process, recent time-resolved infrared spectroscopy experiments on a photoswitchable PDZ domain (PDZ2S) have indicated that the allosteric transition occurs on multiple timescales. Here, using extensive nonequilibrium molecular dynamics simulations, a time-dependent picture of the allosteric communication in PDZ2S is developed. The simulations reveal that allostery amounts to the propagation of structural and dynamical changes that are genuinely nonlinear and can occur in a nonlocal fashion. A dynamic network model is constructed that illustrates the hierarchy and exceeding structural heterogeneity of the process. In compelling agreement with experiment, three physically distinct phases of the time evolution are identified, describing elastic response (≲0.1 ns), inelastic reorganization (∼100 ns), and structural relaxation (≳1μs). Issues such as the similarity to downhill folding as well as the interpretation of allosteric pathways are discussed. [ABSTRACT FROM AUTHOR]

A local perturbation of a proteinmay lead to functional changesat some distal site. An example is the PDZ2 domain of human tyrosinephosphatase 1E, which shows an allosteric transition upon bindingto a peptide ligand. Recently Buchli et al. presented a time-resolvedstudy of this transition by covalently linking an azobenzene photoswitchacross the binding groove and using a femtosecond laser pulse thattriggers the cis–trans photoisomerization of azobenzene. Toaid the interpretation of these experiments, in this work seven microsecondruns of all-atom molecular dynamics simulations each for the wild-typePDZ2 in the ligand-bound and -free state, as well as the photoswitchableprotein (PDZ2S) in the cis and trans states of the photoswitch, inexplicit water were conducted. First the theoretical model is validatedby recalculating the available NMR data from the simulations. By comparingthe results for PDZ2 and PDZ2S, it is analyzed to what extent thephotoswitch indeed mimics the free-bound transition. A detailed descriptionof the conformational rearrangement following the cis–transphotoisomerization of PDZ2S reveals a series of photoinduced structuralchanges that propagate from the anchor residues of the photoswitchvia intermediate secondary structure segments to the C-terminus ofPDZ2S. The changes of the conformational distribution of the C-terminalregion is considered as the distal response of the isolated allostericprotein. [ABSTRACT FROM AUTHOR]

Based on a given time series, the data-driven Langevin equation (dLE) estimates the drift and the diffusion field of the dynamics, which are then employed to reproduce the essential statistical and dynamical features of the original time series. Because the propagation of the dLE requires only local information, the input data are neither required to be Boltzmann weighted nor to be a continuous trajectory. Similar to a Markov state model, the dLE approach therefore holds the promise of predicting the long-time dynamics of a biomolecular system from relatively short trajectories which can be run in parallel. The practical applicability of the approach is shown to be mainly limited by the initial sampling of the system's conformational space obtained from the short trajectories. Adopting extensive molecular dynamics simulations of the unfolding and refolding of a short peptide helix, it is shown that the dLE approach is able to describe microsecond conformational dynamics from a few hundred nanosecond trajectories. In particular, the dLE quantitatively reproduces the free energy landscape and the associated conformational dynamics along the chosen five-dimensional reaction coordinate. [ABSTRACT FROM AUTHOR]

We explore the capability of the non-natural amino acid azidohomoalanine (AHA) as an IR label to sense relatively small structural changes in proteins with the help of 2D IR difference spectroscopy. To that end, we AHA-labeled an allosteric protein (the PDZ2 domain from human tyrosine-phosphatase 1E) and furthermore covalently linked it to an azobenzene-derived photoswitch as to mimic its conformational transition upon ligand binding. To determine the strengths and limitations of the AHA label, in total six mutants have been investigated with the label at sites with varying properties. Only one mutant revealed a measurable 2D IR difference signal. In contrast to the commonly observed frequency shifts that report on the degree of solvation, in this case we observe an intensity change. To understand this spectral response, we performed classical MD simulations, evaluating local contacts of the AHA labels to water molecules and protein side chains and calculating the vibrational frequency on the basis of an electrostatic model. Although these simulations revealed in part significant and complex changes of the number of intraprotein and water contacts upon trans-cis photoisomerization, they could not provide a clear explanation of why this one label would stick out. Subsequent quantum-chemistry calculations suggest that the response is the result of an electronic interaction involving charge transfer of the azido group with sulfonate groups from the photoswitch. To the best of our knowledge, such an effect has not been described before. [ABSTRACT FROM AUTHOR]