## 1 Introduction  
Hemodialysis (HD), also known as renal replacement therapy (RRT), is a procedure to remove extra fluid and uremic toxins from ESRD patients [1, 2]. There is no question that ESRD is a serious public health concern that is inexorably growing. Alongside diabetes and dementia, the mortality rate associated with renal disease has seen a significant increase over the past decade [3, 4]. In contrast, during the same period, global mortality rates for noncommunicable diseases such as heart disease and pulmonary conditions have declined [5, 6]. Polyether sulfone (PES) is the most common HD membrane used in Canadian hospitals and represents 93% of the market. Nevertheless, PES membranes have limited hemocompatibility, which triggers blood activation cascades, and the rate of morbidity and mortality in ESRD patients is still unacceptably high. Thus, there has been significant interest in developing hemocompatible membranes for blood purification. This focus stems from the need to address the primary challenges associated with intra- and posthemodialysis complications, aiming to enhance hemodialysis efficiency and ensure its efficacy for all patients [7, 8, 9]. Due to interactions between human serum proteins and HD membranes, the incompatible HD membrane causes unfavorable biological reactions that start complement, leukocyte, and coagulation bioactivation cascades [10]. When the proper membrane type, material, and surface design are not carefully taken into consideration, the majority of these reactions result in total renal failure, diabetes, fatigue, cardiovascular disorders, and even death [11, 12, 13]. Among different modification techniques, a large number of studies have recently been published in the literature focusing on the zwitterionization of membrane structures to improve their hemocompatibility, which has been intensively studied by our research group [10, 14, 15, 16, 17, 18]. ZW polymers are the last generation of antifouling materials, which have an electrically neutral overall surface charge despite having distinct cationic and anionic groups on each monomer. Such polymeric backbones with an equal number of positive and negative parts are extremely hydrophilic, stable, and hemocompatible and are also an excellent antifouling material [18, 19]. A ZW structure has a large dipole moment and is composed of numerous highly charged groups, which results in exceptional ion conductivity and very strong polarity compared to conventional polymers that do not contain charges [20, 21, 22, 23]. ZW materials have been widely used in anti-biofouling surfaces as the hydration shell around polyzwitterions, which is formed via electrostatic interactions with water molecules that can back away any other biomolecule, including protein chains [24, 25]. The zwitterionic chemical structure influences its polarity, hydrophobicity, hemocompatibility, and anti-polyelectrolyte activity. For instance, it was demonstrated that the length of the carbon spacer (CSL), which is the quantity of -CH2 units separating the opposite charge moieties, can have a significant impact on the ZW characteristics. CSL significantly influences the hydrophilic/hydrophobic balance as well as the flexibility of the ZW backbone, thereby altering its optimized conformation and electrostatic interactions [26, 27, 28, 29]. Additionally, the changing pendant groups and functional groups of ZW have a direct impact on ZW properties [30, 31, 32]. Although various spacer lengths, heads, and other factors have been intensively explored by researchers, none of them have studied the effect of dipole orientation on ZW interactions with human serum proteins and its hemocompatibility, which is one of the most important characteristics of ZWs [33, 34]. The study of protein-ligand interactions as the hemocompatibility indicator is becoming more and more important due to its key role and potential applications in biotechnology and medicine.