How do mutations and allosteric inhibitors modulate caspase-7 activity? A molecular dynamics study

Caspases are members of a highly regulated aspartate-cysteine protease family which have important roles in apoptosis. Pharmaceutical studies focused on these molecules since they are involved in diseases such as cancer and neurodegenerative disorders. A small molecule which binds to the dimeric interface away from the binding site induces a conformational change that resembles the pro-caspase form of the molecule by shifting loop positions. The fluctuation mechanisms caused by mutations or binding of a ligand can explain the key mechanism for the function of that molecule. In this study, we performed molecular dynamics simulations on wild-type and mutated structures (C290N, R187M, Y223A, G188L and G188P) as well as allosterically inhibited structure (DICA-bound caspase-7) to observe the effects of the single mutations on intrinsic dynamics. The results show that previously known changes in catalytic activity upon mutations or allosteric ligand binding are reflected in corresponding changes in the global dynamics of caspase-7.

Communicated by Ramaswamy H. Sarma     

Dynamic conformational changes due to the ATP hydrolysis in the motor domain of myosin: 10-ns molecular dynamics simulations

Muscle contraction is caused by directed movement of myosin heads along actin filaments. This movement is triggered by ATP hydrolysis, which occurs within the motor domain of myosin. The mechanism for this intramolecular process remains unknown owing to a lack of ways to observe the detailed motions of each atom in the myosin molecule. We carried out 10-ns all-atom molecular dynamics simulations to investigate the types of dynamic conformational changes produced in the motor domain by the energy released from ATP hydrolysis. The results revealed that the thermal fluctuations modulated by perturbation of ATP hydrolysis are biased in one direction that is relevant to directed movement of the myosin head along the actin filament.     

A continuum model to study the internal fluctuations in globular proteins

The salient features of the differential equation model to study protein dynamics are presented with results for 19 proteins.     

Picosecond timescale rigid-helix and side-chain motions in deoxymyoglobin

The contribution of rigidbody motions to the atomic trajectories in a 100 ps molecular dynamics simulation of deoxymyoglobin is examined. Two typesof rigid-body motions are considered: one in which the helices are rigid units and one in which the side-chains are rigid units. Using a quaternionbased algorithm, fits of the rigid reference structures are made to each time frame of the simulation to derive trajectories of the rigid-body motions. The fitted trajectories are analysed in terms of atomic position fluctuations, mean-square displacements as a function of time, velocity autocorrelation functions and densities of states. The results are compared with the corresponding quantities calculated from the full trajectory. The relative contribution of the rigid helix motions to the helix atom dynamics depends on which quantity is examined and on which subset of atoms is chosen: rigid-helix motions contribute 86% of the rms helix backbone atomic position fluctuations, but 30% of the helix,: atom (backbone and side-chain) mean square displacements and only 1.1% of total kinetic energy. Only very low-frequency motions contribute to the rigid-helix dynamics; the rigid-body analysis allows characteristic rigid-helix vibrations to be identified and described. Treating the side-chains as rigid bodies is foundto be an excellent approximation to both their diffusive and vibrationalmean-square displacements: 96% of side-chain atom mean-square displacements originate from rigid side-Chain motions. However, the errors in theside-chain atomic positional fits are not always small. An analysis is madeof factors contributing to the positional error for different types of side-chain. © Wiley-Liss, Inc.     

Solution Conformation of [D-Pen2,D-Pen5]enkephalin in Water: A NMR and Molecular Dynamics Study

The solution conformation of [D -Pen²,D -Pen⁵] enkephalin (DPDPE), a highly potent δ-selective opioid agonist, was examined by means of NMR, molecular mechanics and molecular dynamics methods. The structural information in the solvent water was obtained employing one- and two-dimensional methods of ¹H and ¹³C-NMR spectroscopy. Based on the distance geometry technique using the ROE data as input, 400 conformers were obtained and considered in the structure analysis. Alternatively, about 2000 conformers were stochastically generated and related to the NMR data after energy minimization. The structure analysis provides one conformer in agreement with all NMR data, which belongs to the lowest energy conformation group. This structure may serve as a reference conformer for DPDPE analogues synthesized with the aim of activity increase.     

Collective motions in proteins: a covariance analysis of atomic fluctuations in molecular dynamics and normal mode simulations.

A method is described for identifying collective motions in proteins from molecular dynamics trajectories or normal mode simulations. The method makes use of the covariances of atomic positional fluctuations. It is illustrated by an analysis of the bovine pancreatic trypsin inhibitor. Comparison of the covariance and cross-correlation matrices shows that the relative motions have many similar features in the different simulations. Many regions of the protein, especially regions of secondary structure, move in a correlated manner. Anharmonic effects, which are included in the molecular dynamics simulations but not in the normal analysis, are of some importance in determining the larger scale collective motions, but not the more local fluctuations. Comparisons of molecular dynamics simulations in the present and absence of solvent indicate that the environment is of significance for the long-range motions.