Interactions between molecules are ubiquitous and occur in our bodies, the food we eat, the air we breathe, and myriad additional contexts. Although numerous tools are available for the recognition of biomolecular interactions, such tools are often limited in their sensitivity, expensive, and difficult to modify for various uses. In contrast, the quartz crystal microbalance (QCM) has sub-nanogram detection capabilities, is label-free, is inexpensive to create, and can be readily modified with a number of diverse surface chemistries to detect and characterize diverse interactions. To maximize the versatility of the QCM, scientists need to know available methods by which QCM surfaces can be modified. Therefore, in addition to summarizing the various tools currently used for biomolecular recognition, explicating the fundamental principles of the QCM as a tool for biomolecular recognition, and comparing the QCM with other acoustic sensors, we systematically review the numerous types of surface chemistries-including hydrophobic bonds, ionic bonds, hydrogen bonds, self-assembled monolayers, plasma-polymerized films, photochemistry, and sensing ionic liquids-used to functionalize QCMs for various purposes. We also review the QCM's diverse applications, which include the detection of gaseous species, detection of carbohydrates, detection of nucleic acids, detection of non-enzymatic proteins, characterization of enzymatic activity, detection of antigens and antibodies, detection of cells, and detection of drugs. Finally, we discuss the ultimate goals of and potential barriers to the development of future QCMs.

alpha(1)-Antitrypsin (AT) is a major proteinase inhibitor within the lung. The Z variant of AT (E342K) polymerizes within the liver and lung, resulting in hepatic aggregation of AT and tissue deficiency, predisposing to early onset of cirrhosis and emphysema, respectively. Polymerization of the aberrant protein can be prevented in vitro by specific peptides such as FLEAIG. This peptide serves as a lead molecule to design a shorter peptide that may be effective as a therapeutic agent. In this study we employed a systematic chemical approach using alanine scanning of Ac-FLEAIG-OH and subsequent peptide shortening to study the binding of shorter peptides to Z-AT. While two additional 6-mer peptides Ac-FLAAIG-OH and Ac-FLEAAG-OH were found to bind to Z-AT, their daughter peptides Ac-FLEAA-NH(2) and Ac-FLAA-NH(2) also bound avidly to Z-AT and prevented polymerization of the protein. Further comparative studies revealed that the binding of Ac-FLAA-NH(2) was more specific for Z-AT. The peptide-AT complex formation was enhanced by the presence of C-terminal amide group on the peptide, and circular dichroism analysis demonstrated that a random coil rather than a beta-helical conformation favored binding of the peptide to AT. In summary, this study has identified novel small peptides that inhibit Z-AT polymerization, and are a significant advance towards the treatment of Z-AT-related cirrhosis and emphysema.

IntroductionThe ␣1-antitrypsin (AT) is the most abundant circulating protease inhibitor in plasma (1-2 mg/ml) and a prototypical member of the serpin (serine protease inhibitor) superfamily [1,2]. It is primarily synthesized by the hepatocyte and enters the lung by passive diffusion to protect the alveolar matrix from proteolysis, particularly by neutrophil elastase [1][2][3][4][5][6]. The secondary structure of active AT is composed of three ␤-sheets (A, B and C), nine ␣-helices (A-I), and a reactive centre loop (RCL) which tightly entraps neutrophil elastase and other target proteases [6][7][8] [10][11][12]. The accumulation of Z-AT polymers within the hepatocyte causes liver cirrhosis and the resultant plasma deficiency can give rise to early-onset emphysema [13][14][15][16][17]. Polymerization of other serpin variants such as those of antithrombin III, ␣1-antichymotrypsin, C1-inhibitor and neuroserpin have also been described and related to thrombosis, emphysema, angioedema and dementia, respectively [18, 19]. [18,[20][21][22][23][24] Given that protein aggregation is the origin for the pathogenesis of the liver and lung diseases associated with Z-AT, the crux of the matter is to inhibit the oligomerization process and thus prevent the intracellular accumulation of Z-AT polymers. Previous studies have shown that 11-to 13-mer synthetic peptides with homology to the RCL could anneal to the A-sheet of AT