Tagging and tracking protein molecules are a key to a better understanding of proteomics in diverse aspects. In this paper, a common framework of particle filter using optimal importance function is proposed for confocal protein molecules tracking. To deal with the challenges stemming from small size, deformable shape, noisy environment, and multi-modality motion, a stochastic process based particle filter is used. Partial Gaussian State Space (PGSS) model is developed as the importance function to incorporate the latest measurement in the state estimation. Experimental results have demonstrated the performance of the proposed algorithm for both Brownian and translational motion.