BIOMOLECULAR DYNAMICS AT LONG TIMESTEPS:Bridging the Timescale Gap Between Simulation and Experimentation

Abstract

Innovative algorithms have been developed during the past decade for simulating Newtonian physics for macromolecules. A major goal is alleviation of the severe requirement that the integration timestep be small enough to resolve the fastest components of the motion and thus guarantee numerical stability. This timestep problem is challenging if strictly faster methods with the same all-atom resolution at small timesteps are sought. Mathematical techniques that have worked well in other multiple-timescale contexts--where the fast motions are rapidly decaying or largely decoupled from others--have not been as successful for biomolecules, where vibrational coupling is strong. This review examines general issues that limit the timestep and describes available methods (constrained, reduced-variable, implicit, symplectic, multiple-timestep, and normal-mode-based schemes). A section compares results of selected integrators for a model dipeptide, assessing physical and numerical performance. Included is our dual timestep method LN, which relies on an approximate linearization of the equations of motion every delta t interval (5 fs or less), the solution of which is obtained by explicit integration at the inner timestep delta tau (e.g., 0.5 fs). LN is computationally competitive, providing 4-5 speedup factors, and results are in good agreement, in comparison to 0.5 fs trajectories. These collective algorithmic efforts help fill the gap between the time range that can be simulated and the timespans of major biological interest (milliseconds and longer). Still, only a hierarchy of models and methods, along with experimentational improvements, will ultimately give theoretical modeling the status of partner with experiment.

Dynamics of C60Molecules in Biological Membranes: Computer Simulation Studies

“…Such simulations have been successfully applied, for example, to enzyme reactions, protein folding, ion channels, and membrane fusion. [24][25][26][27][28][29][30][31] Computer simulation studies for the interaction between carbon nanoparticles and biological materials such as proteins and DNA have also been performed. [32][33][34][35][36][37][38] The inhibition of the HIV-1 protease by fullerenes and their derivatives 32,[36][37] was studied and the binding behavior of carbon nanotubes with nucleic acids 34,38 or amylose 33 was also investigated to improve the solubility of nanotubes.…”

Conformational changes in the chaperonin GroEL: new insights into the allosteric mechanism 1 1Edited by A. R. Fersht

“…The most common method to study conformational¯uctuations in proteins is molecular dynamics (MD), but with a molecular mass of 800 kDa it would be an impossible task to reach biologically relevant time-scales when realistic force-®elds are being used. A number of methods exists to speed up the ef®ciency of conformational sampling in MD (Berne & Straub, 1997;Schlick et al, 1997), and other computational techniques are also avialable. Ma & Karplus (1998) recently performed normal mode calculations on a minimal subsystem (three subunits) of GroEL that could provide insight into its allosteric mechanism.…”

Ribosome Builder: A software project to simulate the ribosome

“…However, there is another more specific and immediate goal that has determined the development of the Ribosome Builder software. This goal is concerned with solving something known as 'the timestep' problem, because it has to do with an important limitation in existing molecular dynamics software where the activity that can currently be simulated is confined to very small time intervals compared to what is needed (Schlick et al, 1997). A significant portion of the Ribosome Builder project is a methodology for overcoming this timestep limitation.…”