Gokara Mahesh, Kimavath Geetha Bai, Podile Appa Rao, Subramanyam Rajagopal
a Department of Biochemistry , School of Life Sciences, University of Hyderabad , Hyderabad 500046 , India.
J Biomol Struct Dyn. 2015;33(1):196-210. doi: 10.1080/07391102.2013.868321. Epub 2013 Dec 20.
Chitosan is a naturally occurring deacetylated derivative of chitin with versatile biological activities. Here, we studied the interaction of chitosan oligomers with low degree of polymerization such as chitosan monomer (CM), chitosan dimer (CD), and chitosan trimer (CT) with human serum albumin (HSA) a major blood carrier protein and α-1-glycoprotein (AGP). Since, HSA and AGP are the two important plasma proteins that determine the drug disposition and affect the fate of distribution of drugs. Fluorescence emission spectra indicated that CM, CD, and CT had binding constants of KCM = 6.2 ± .01 × 10(5) M(-1), KCD = 5.0 ± .01 × 10(4) M(-1), and KCT = 1.6 ± .01 × 10(6) M(-1), respectively, suggesting strong binding with HSA. However, binding of chitooligomers with AGP was insignificant. Thermodynamic and molecular docking analysis indicated that hydrogen bonds and also hydrophobic interaction played an important role in stabilizing the HSA-chitooligomer complexes with free energies of -7.87, -6.35, and -8.4 Kcal/mol for CM, CD, and CT, respectively. Further, circular dichroism studies indicated a minor unfolding of HSA secondary structure, upon interaction with chitooligomers, which are supported with fluctuations of root mean square deviation (RMSD) and radius of gyration (Rg) of HSA. Docking analysis revealed that all three chitooligomers were bound to HSA within subdomain IIA (Site I). In addition, RMSD and Rg analysis depicted that HSA-chitooligomer complexes stabilized at around 4.5 ns. These results suggest that HSA might serve as a carrier in delivering chitooligomers to target tissues than AGP which has pharmacological importance.
壳聚糖是一种天然存在的几丁质脱乙酰衍生物，具有多种生物活性。在此，我们研究了低聚合度的壳聚糖低聚物，如壳聚糖单体（CM）、壳聚糖二聚体（CD）和壳聚糖三聚体（CT）与人血清白蛋白（HSA，一种主要的血液载体蛋白）和α-1-糖蛋白（AGP）的相互作用。因为，HSA和AGP是两种重要的血浆蛋白，它们决定药物处置并影响药物的分布命运。荧光发射光谱表明，CM、CD和CT的结合常数分别为KCM = 6.2 ± 0.01 × 10(5) M(-1)、KCD = 5.0 ± 0.01 × 10(4) M(-1)和KCT = 1.6 ± 0.01 × 10(6) M(-1)，表明它们与HSA有强烈结合。然而，壳聚糖低聚物与AGP的结合不显著。热力学和分子对接分析表明，氢键以及疏水相互作用在稳定HSA-壳聚糖低聚物复合物中起重要作用，CM、CD和CT的自由能分别为-7.87、-6.35和-8.4千卡/摩尔。此外，圆二色性研究表明，与壳聚糖低聚物相互作用时，HSA二级结构有轻微展开，这得到了HSA的均方根偏差（RMSD）和回转半径（Rg）波动的支持。对接分析显示，所有三种壳聚糖低聚物都在亚结构域IIA（位点I）内与HSA结合。此外，RMSD和Rg分析表明，HSA-壳聚糖低聚物复合物在约4.5纳秒时稳定。这些结果表明，与具有药理学重要性的AGP相比，HSA可能作为载体将壳聚糖低聚物递送至靶组织。
