Environmental Factors - ARTICLE ARTICLE Environmental Factors can Modify Genotype Risks by Slight Changes in Protein Conformation: The Role of Water Shahram Shahabi 1 *, Zuhair Muhammad Hassan 2 , Nima Hosseini Jazani 1 , Massoumeh Ebtekar 2 1 Department of Immunology, Microbiology and Genetics, Faculty of Medicine, Urmia University of Medical Sciences, Urmia, Iran. 2 Department of Immunology, Faculty of Medical Sciences, Tarbiat Modarres University, Tehran, Iran. Correspondence: s_shahabi@umsu.ac.ir; shahabirabori@yahoo.com In biological systems, water is not simply arranged, but is highly structured. Interactions between structured water and proteins have an important role in the preservation of protein conformation, which is vital for their proper function. Any agent that can exert a direct effect on an organism might also change the structure of water molecules, resulting in slight changes in protein conformation. In disease states, these changes could efficiently target the proteins that are products of mutated genes, but display normal, or approximately normal, functions in a normal environment. Physiological compensatory agents such as stress proteins can correct abnormal protein conformation. However, if slightly altered conformations of proteins (due to altered water structure) persist, they may not be able to be restructured by stress proteins, resulting in abnormal protein function. The purpose of this paper is to provide a hypothesis for a mechanism through which protein structure and function is modulated by altering the surrounding water microenvironment. Introduction A multifactorial disease is a disorder caused by the interaction of genetic and non- genetic, environmental factors. Therefore, the development of a multifactorial disease requires both a specific genotype factor and a suitable environment. The routes by which the environment affects the onset or course of a disease vary depending on environmental factors (1). Proteins are often a favoured target of these factors. At the molecular scale, proteins carry out the essential physiological processes, and are thus fascinating molecular devices. They play a variety of roles in life processes; there are structural proteins, catalytic proteins, transport and storage proteins, regulatory proteins and proteins of the immune system and the immunoglobulin superfamily (2). Proteins have a three-dimensional structure and their function is completely dependent on this structure (2,3). The most important target of stressors is the conformation of proteins, while the primary aim of the stress response of biological systems is to inhibit or to reverse this conformational change (2,3). However, the question remains: how do these environmental factors affect proteins? The effects may be exerted in a direct manner. For example, the concentration of an important ion in the synthesis or function of a protein will naturally affect the functions of that protein (4). Yet, their direct effects cannot explain all consequences of environmental stressors. The purpose of this paper is to provide a hypothesis for a mechanism through which environment can affect protein function. Water is the most abundant molecule in living cells, and scientific evidence indicates that this simple molecule has an important role in more than merely inter-molecular interactions. Water is the only solvent in biological systems, and all biological activities are performed in water (5). Therefore, water may be a very good medium through which the effects of environmental pressures are transferred to proteins in a biological system. Hypothesis - 7