(209a) A Computer Simulation and Theoretical Study of Hybridization in Model DNA Microarrays

DNA microarrays have been widely adopted by the scientific community for a variety of applications. In order to improve the performance of microarrays there is a need for a fundamental understanding of the interplay between the various factors that affect microarray sensitivity and specificity. We use simulation and theory to study the thermodynamics and kinetics of hybridization of single stranded ?target? genes in solution with complementary ?probe? DNA molecules immobilized on a microarray surface. We use lattice Monte Carlo simulations to examine how the probe length, surface density (number of probes per unit surface area) and concentration of target molecules affect the extent of hybridization. The targets and the probes are modeled as chains of distinct segments where each segment represents a sequence of nucleotides. Each probe segment interacts exclusively with its unique complementary target segment with a single hybridization energy; all other interactions are zero. For systems with a single probe binding to a single target, as the probe length increases, the probability of finding the target segments bound to all probe segments (specificity) decreases. For short probe lengths we observe an optimum surface density that gives the highest specificity.

We use spin-1/2 theory to study the kinetics of probe-target hybridization by obtaining a mathematical expression for a time correlation function c(l,t) that predicts the state of the j±l^th probe segment at time t with respect to the state of the j^th segment at time 0. Every probe segment can in be one of two states: bound state (+1) and unbound state (-1). The time correlation function c(l,t) explains how the hybridization progresses through the probe from the point of nucleation (the segment that starts the hybridization) and thus explains the mechanism of probe-target hybridization.