丝氨酸(S13和S14)残基侧链位置特性对模型蛋白Trp-cage折叠的影响

Computational studies on the influence of orientation properties of two serine(S13 and S14)side chains on the Trp-cage folding dynamics using a residue-specific force field

以模型蛋白Trp-cage为例,采用基于PDB卷曲库优化现有OPLSAA/L后得到的残基特异性力场(RSFF1)研究野生态模型蛋白Trp-cage及其突变体S13G和S14G的折叠转变过程。结果表明:野生态结构在RSFF1力场下能够快速准确地折叠至天然态(RMSD=0.67 A),其折叠路径为D■I1■I2■N,符合扩散-碰撞模型。侧链朝向溶剂的残基S13突变后并未对其二级和三级结构的形成产生较大影响,且其结构最终折叠形成近天然态N’(RMSD=1.9 A);而侧链朝向结构内部的残基S14则不同,其残基突变后导致结构N端α-螺旋局部结构解旋松散、310-螺旋结构消失,并且三级疏水核心结构错误塌缩(RMSD=3.8 A)。具有相同侧链的残基S13和S14由于其侧链朝向相反对其结构稳定和折叠转变的贡献程度不同,这表明在稳定多肽和蛋白活性构象和提高多肽类抑制剂成药性过程中除了研究残基侧链本身的电荷、疏水、极性等化学特性还需充分考虑到残基侧链自身的朝向位置特性。

The Trp-cage mini-protein has been taken as an example to study the influence of orientation properties of two serine side chains on its folding dynamics using a residue-specific force field(RSFF1).It was obtained by improving the current OPLSAA/L force field through adding some special non-bonded interactions based on statistical analysis of intrinsic conformational features of coil regions in protein structures(PDB coil library).The folding process of wild-type Trp-cage and its two mutations(S13G and S14G)were reproduced.It was found that this modified force field(RSFF1)could fold wild-type Trp-cage to its natively folded structure(N)with a low RMSD of only c.a.0.67?,which resembled the experimental structure.Its folding pathway could be decomposed into three steps:D■I1■I2■N,where D,I and N represented the denatured state,intermediate and natively folded state,respectively.The folding mechanism was in accordance with the diffusion collision model.Instead,only slight influences on secondary and tertiary structures were induced by mutation S13 G,and the structure could arrive at the native-like state(N’)with a RMSD of c.a.1.9?.The S14G mutation exerted observable influences on the folding dynamics.The N-terminalα-helices were locally loose,the destroy of 310-helices and hydrophobic collapses were concomitant in the S14G mutation,resulting a mis-folded state with a RMSD of c.a.3.8?.Because S13 and S14 with the same side-chain exhibited the opposite orientation,their contributions to its structural stability and folding dynamics showed obvious discrepancy.It implied that both chemical(such as charge,hydrophobicity and polarity etc.)and orientation properties of side chains themselves should be fully considered during stabilizing active conformation of polypeptide/protein and improving the drugg ability of peptide inhibitor.