High-speed molecular mechanics searches for optimal DNA interaction sites.

We have recently developed a theoretical means of studying the mechanical and interaction properties of nucleic acids as a function of their base sequence. This approach, termed ADAPT, can be used to obtain the physical properties of millions of base sequences with only modest computational expense. ADAPT is based on a multi-copy algorithm using special nucleotides ("lexides") containing all four standard bases whose contribution to the energy of the molecule can be varied. We present here a deeper study of the energy minima which occur in the multi-dimensional space defined by these variable sequences. We also present an extension of the approach termed "gene threading" which enables us to scan genomic sequence data in an attempt to locate preferential binding sites. This technique is illustrated for the case of TATA-box protein binding. ADAPT enables us to demonstrate that, for this protein, DNA deformation alone explains a large part of the experimentally observed consensus binding sequence.

Optimization of nucleic acid sequences.

Base sequence influences the structure, mechanics, dynamics, and interactions of nucleic acids. However, studying all possible sequences for a given fragment leads to a number of base combinations that increases exponentially with length. We present here a novel methodology based on a multi-copy approach enabling us to determine which base sequence favors a given structural change or interaction via a single energy minimization. This methodology, termed ADAPT, has been implemented starting from the JUMNA molecular mechanics program by adding special nucleotides, "lexides," containing all four bases, whose contribution to the energy of the system is weighted by continuously variable coefficients. We illustrate the application of this approach in the case of double-stranded DNA by determining the optimal sequences satisfying structural (B-Z transition), mechanical (intrinsic curvature), and interaction (ligand-binding) properties.

ADAPT: a molecular mechanics approach for studying the structural properties of long DNA sequences.

We describe an original approach to determining sequence-structure relationships for DNA. This approach, termed ADAPT, combines all-atom molecular mechanics with a multicopy algorithm to build nucleotides that contain all four standard bases in variable proportions. These nucleotides enable us to search very rapidly for base sequences that energetically favor chosen types of DNA deformation or chosen DNA-protein or DNA-ligand interactions. Sequences satisfying the chosen criteria can be found by energy minimization, combinatorial sequence searching, or genome scanning, in a manner similar to the threading approaches developed for protein structure prediction. In the latter case, we are able to analyze roughly 2000 base pairs per second. Applications of the method to DNA allomorphic transitions, DNA deformation, and specific DNA interactions are presented.

Collective variable modelling of nucleic acids.

Collective variable models continue to contribute to our knowledge of nucleic acids. The past year has seen considerable progress both in modelling sequence-dependent effects on nucleic acid conformation and in understanding how proteins or external stresses influence nucleic acid structure. Algorithmic developments have also allowed collective models to be applied to studies of thermal fluctuations and dynamics. For larger systems, models with varying degrees of resolution are being refined and applied to nucleic acids containing hundreds or thousands of nucleotides.