| With suitable force fields and integration protocols, computer simulations of large biomolecular systems can offer insights into molecular structure, flexibility and functionality. Scientists are continuously trimming down algorithmic cost to economize code performance while enhancing the biological models with more detail and realism. In our work, we address some fundamental aspects in biomolecular simulation methodology: (i) proper implemention of mathematical machinery to mimic realistic thermodynamic ensembles (Chapter 1); (ii) the design of accurate and efficient multiple-timestep (MTS) integrators tailored for Ewald electrostatic formulations (Chapter 2 and 3); and (iii) the preparation of an efficient space-filling periodic boundary model to handle various domains (Chapter 4). These investigations have produced a program (PBCAID) to initialize and optimize a periodic lattice specified as one of several known space-filling polyhedra, which leads to computational savings in the nonbonded computations from reduced solvent sizes, our resonance and stability analysis for different Verlet integrators have provided guidelines for designing new MTS integrators; indeed, a new efficient MTS force splitting scheme for particle-mesh-Ewald molecular dynamics simulations, was developed and implemented in the Amber program, exhibiting good speedup and excellent stability.; As an application of these combined algorithmic developments, we explore the fundamental relationship between DNA sequence/deformability and biological function (Chapter 5) for a classic regulatory system, the complex between the TATA element transcriptional regulator and TBP (TATA-Box Binding Protein). We present the molecular dynamics simulation results of 13 TATA variants that differ by a single base pair, and analyze sequence-dependent structural, energetic, and flexibility properties that tailor TATA elements to TBP interactions. Such factors include overall flexibility; minor groove widening, as well as roll, rise, and shift increases at the ends of the TATA element; untwisting throughout the DNA; and relatively low maximal water densities around the DNA. These structural patterns, identified here and connected to a new crystallographic study of a larger group of DNA variants that reported to date, highlight the profound influence of single base pair DNA variations on structure, flexibility, and hydration preferences and the evolutionary complementarity between DNAs and proteins in binding and activity. |
