蛋白質是由一個或多個胺基酸高分子鏈所組成並在生物系統中扮演各種重要的角色。蛋白質的功能和其三維結構高度相關，而蛋白質結構易受外在環境因素影響，如溶液酸鹼值、溫度、濃度等。許多生化反應與應用涉及蛋白質的界面吸附，例如材料表面改質的添加劑、細胞培養、或是生物感測器探測分子等。因此了解與預測蛋白質吸附於界面的折疊結構對於其功能調控極為重要。先前有研究，運用理論吸附的模型搭配分子動態模擬，快速估計蛋白質於溶液中以及在氣液界面的構型自由能差距，用以驗證蛋白質於界面摺疊與吸附之熱力學關係。然而，此吸附模型雖然可以準確估計出不同構型吸附於氣液界面之自由能之差值，但其所估計之吸附自由能有著1至2個數量級之誤差，在此研究中，修正了蛋白質吸附模型，並將吸附自由能之計算分為兩大部分：(1) 蛋白質水合自由能與 (2) 蛋白質於氣液界面所造成氣液界面自由能變化。運用分子模擬，先建構精確的水合自由能與水合表面積之關聯，用以計算20種胺基酸之水合自由能。運用此資料庫進而計算出整個蛋白質之水合自由能。在考慮毛細力和線張力對界面之作用後，亦修正了氣液界面自由能。綜合上述二種熱力學校正因素，此模型可準確地估算出蛋白質以α螺旋與β髮夾之結構的吸附自由能至10%以內之誤差。運用此模型也探討了類澱粉蛋白短鏈的纖維結構從三聚體到六聚體於氣液界面的吸附機制，其結果顯示所排開的氣液接觸所造成的自由能變化，是類澱粉蛋白吸附於界面的主要驅動力。此模型更可進一步應用於蛋白質吸附於生物雙層膜表面(1,2-dioleoyl-sn-glycero-3-phosphocholine (DOPC))，並準確的估算出其從水相移動到膜表面的吸附自由能分布。本研究所建構之蛋白質吸附模型，有利於瞭解蛋白質於界面之結構變化，將有助於日後生化工程等領域之發展。

Proteins are biopolymers with many important biological functions such as structural supports, catalysis, and cell signaling, etc. Applications of proteins, e.g. sensors and biocatalysts, require them to function at interfaces. Since the function of a protein is directly related to its 3-dimentional folding structure, understanding the protein conformational preference at the interface is critical for their application designs. Previous study derived a fast and accurate estimation of protein conformational preference changes when adsorbed at air/water interface using molecular dynamics (MD) simulations and the experimental solvation free energy data. Despite of the accurate estimation of the adsorption free energy difference between two protein conformations, the value for each adsorption free energy is overestimated by 1-2 orders. Here, we re-derived the de-solvation and the interfacial energy terms to provide a more accurate adsorption free energy estimation. Using MD simulation, we mapped the solvent accessible surface area (SASA) with the ideal free energy to identify the direct relation between them. This allowed us to construct the de-solvation free energy and SASA database for 20 amino acids, allowing the further estimation of protein de-solvation free energy. For the interfacial energy, we corrected the surface tension using the factor, k, related to the effects of surface meniscus and line tension at interface. The refined estimation resulted in greatly improved adsorption free energy estimations with less than 10% error for polyalanine and GB1 peptide in both α–helix and β-hairpin conformations. This model was further applied to investigate the adsorption free energy of small amyloid peptide fibrils at air/water interface. Our results showed that the fibril tends to adsorb at the air/water interface due to the reduction of adsorption free energy from trimer to hexamer. We also extended the new adsorption model to estimate adsorption free energy of protein at the water/DOPC bilayer interface. The resulting energy profiles of α-helical and β-strand polyalanine were in excellent agreement with the reference umbrella sampling free energy profiles.

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