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Molecular dynamics trajectories of large biological molecules are restricted to nanoseconds. We describe a computational method, based on optimization of a functional, to extend the time of molecular simulations by orders of magnitude. Variants of our technique have already produced microsecond and millisecond trajectories. The large steps enable feasible computations of atomically detailed approximate trajectories. Numerical examples are provided:  (i) a conformational change in blocked glycine peptide and (ii) helix formation of an alanine-rich peptide.

The design of chemical compounds for development of latent fingerprints is explored computationally. Our main findings are: (a) We show why past attempts to improve the widely used ninhydrin gave relatively small improvements (referring to color only). The optical transition is connected with a “transition core” and therefore is influenced little by substitution on the aromatic rings. (b) We propose new analogues of ninhydrin with a significant potential such as thiono derivatives.

A novel method to compute long-time molecular dynamics trajectories is employed to study the folding kinetics of C peptide. The computational method makes it possible to use a time step larger by orders of magnitude compared to widely used molecular dynamics integrators. Rather than solving the trajectory in small time steps, the whole trajectory is optimized. The algorithm filters high-frequency modes that are modeled as Gaussian noise. The assumption of “Gaussian noise” is tested numerically in two cases and found to be adequate. In all, 31 trajectories of C peptide that folds into a helix in explicit solvent (TIP3P water molecules) are computed. The time step is 500 ps. The folding pathways and the early formation of structure are discussed. Comparisons to a 2-ns trajectory calculated with the usual molecular dynamics approach and to available experimental data are made.

Conformational transitions between the 112 stable states of the tetrapeptide isobutyryl-Ala3-NH-methyl (IAN) are studied theoretically. The objective of the investigation is to advance the understanding of helix formation and of conformational transitions in polypeptides. The possible reaction paths between extended chain and helical configurations are examined in detail. The study of the multiple reaction paths in this 48-atom molecule became possible due to development of a new computational algorithm. It is shown that the helix-coil transitions in IAN follow a sequence of local dihedral flips and that the number of the available routes for the transition is significantly lower than in a random search. A quasi-melting point is obtained at 5 +/- 1 kcal (1 cal = 4.18 J)/mol above the lowest energy minimum. Below this point the molecule is trapped in one or very few minima, and above it the molecule hops between a large number of configurations.