Computational Biology and Chemistry 31 (2007) 99–109 A kinetic Monte Carlo simulation study of inositol 1,4,5-trisphosphate receptor (IP3R) calcium release channel H.H. Haeri a,∗ , S.M. Hashemianzadeh b , M. Monajjemi c a Department of Physical Chemistry, Central Tehran Campus (Tehran Shargh Branch), Islamic Azad University, P.O. Box 33955/163, Tehran, Iran b Department of Physical Chemistry, Iran University of Science and Technology (IUST), Tehran, Iran c Department of Physical Chemistry, Science and Research Campus, Islamic Azad University, Tehran, Iran Received 4 September 2006; accepted 14 February 2007 Abstract Most of the previously theoretical studies about the stochastic nature of the IP3R calcium release channel gating use the chemical master equation (CME) approach. Because of the limitations of this approach we have used a stochastic simulation algorithm (SSA) presented by Gillespie. A single subunit of De Young–Keizer (DYK) model was simulated using Gillespie algorithm. The model has been considered in its complete form with eight states. We investigate the conditions which affect the open state of the model. Calcium concentrations were the subject of fluctuation in the previous works while in this study the population of the states is the subject of stochastic fluctuations. We found out that decreasing open probability is a function of Ca 2+ concentration in fast time domain, while in slow time domain it is a function of IP3 concentration. Studying the population of each state shows a time dependent reaction pattern in fast and medium time domains (10 -4 and 10 -3 s). In this pattern the state of X 010 has a determinative role in selecting the open state path. Also, intensity and frequency of fluctuations and Ca 2+ inhibitions have been studied. The results indicate that Gillespie algorithm can be a better choice for studying such systems, without using any approximation or elimination while having acceptable accuracy. In comparison with the chemical master equation, Gillespie algorithm is also provides a wide area for studying biological systems from other points of view. © 2007 Elsevier Ltd. All rights reserved. Keywords: Ion channel; De Young–Keizer model; Stochastisity; Gillespie algorithm; Monte Carlo; Complex reactions 1. Introduction The importance of calcium in cell biology was first discussed by Sidney Ringer in 1882. He demonstrated that minute amounts of the divalent ion were necessary to maintain heart muscle con- tractility (Ringer, 1883) and today the specialist are believed that ‘Almost everything that we do is controlled by Ca 2+ : how we move, how our hearts beat and how our brains process informa- tion and store memories’ (Berridge, 1990). There are many other processes that can be add to this list, such as how eggs are acti- vated upon fertilization, how acinar cells secrete, how wounds heal, how ciliary beat frequency is coordinated, how liver cells coordinate their behavior and how cells die in apoptosis (Falcke, 2004). ∗ Corresponding author. E-mail address: hashemihaeri@gmail.com (H.H. Haeri). In a cellular view, calcium ion is an important second mes- senger in cells. There are many cellular processes that can be activated by Ca 2+ . They have evolved to be Ca 2+ -dependent and/or Ca 2+ -regulated, such as protein kinases, protein phos- phatases, proteases, pumps and channels, cytoskeletal compo- nents and enzymes involved in metabolism. Second messengers also play an important role in control- ling the functioning of all cells of the body by acting as carriers of intracellular messages. Cells receive their instructions from the body through hormones and neurotransmitters that bind to receptors on their surface. Many of these messages are relayed by the release of calcium ions from internal stores into the cell cytoplasm, or by opening channels in the membrane of the cell, allowing external calcium to enter the cytoplasm. In the other words calcium controls a wide range of cellular functions such as neurotransmitter and hormone release, muscle contraction, metabolism, cell death, cell division, cell motility and gene expression. Also, Ca 2+ ions are completely remarkable in the ability of controlling numerous processes within the same cell 1476-9271/$ – see front matter © 2007 Elsevier Ltd. All rights reserved. doi:10.1016/j.compbiolchem.2007.02.009