Response of rotation-translation blocked proteins using Langevin dynamics on a locally harmonic landscape

Langevin dynamics is used to compute the time evolution of the nonequilibrium motion of the atomic coordinates of a protein in response to ligand dissociation. The protein potential energy surface (PES) is approximated by a harmonic basin about the minimum of the unliganded state. Upon ligand dissociation, the protein undergoes relaxation from the bound to the unbound state. A coarse graining scheme based on rotation translation blocks (RTB) is applied to the relaxation of the two domain iron transport protein, ferric binding protein. This scheme provides a natural and efficient way to freeze out the small amplitude, high frequency motions within each rigid fragment, thereby allowing for the number of dynamical degrees of freedom to be reduced. The results obtained from all flexible atom (constraint free) dynamics are compared to those obtained using RTB-Langevin dynamics. To assess the impact of the assumed rigid fragment clustering on the temporal relaxation dynamics of the protein molecule, three distinct rigid block decompositions were generated and their responses compared. Each of the decompositions was a variant of the one-block-per-residue grouping, with their force and friction matrices being derived from their fully flexible counterpart. Monitoring the time evolution of the distance separating a selected pair of amino acids, the response curves of the blocked decompositions were similar in shape to each other and to the control system in which all atomic degrees of freedom are fully independent. The similar shape of the blocked responses showed that the variations in grouping had only a minor impact on the kinematics. Compared with the all atom responses, however, the blocked responses were faster as a result of the instantaneous transmission of force throughout each rigid block. This occurred because rigid blocking does not permit any intrablock deformation that could store or divert energy. It was found, however, that this accelerated response could be successfully corrected by scaling each eigenvalue in the appropriate propagation matrix by the least-squares fitted slope of the blocked vs nonblocked eigenvalue spectra. The RTB responses for each test system were dominated by small eigenvalue overdamped Langevin modes. The large eigenvalue members of each response dissipated within the first 5 ps, after which the long time response was dominated by a modest set of low energy, overdamped normal modes, that were characterized by highly cooperative, functionally relevant displacements. The response assuming that the system is in the overdamped limit was compared to the full phase space Langevin dynamics results. The responses after the first 5 ps were nearly identical, confirming that the inertial components were significant only in the initial stages of the relaxation. Since the propagator matrix in the overdamped formulation is real-symmetric and does not require the inertial component in the propagator, the computation time and memory footprint was reduced by 1 order of magnitude.