Circadian rhythm is a biological cycle that is involved in all processes over 24 h day and night period. Sirtuin 1 (SIRT1) is a 747 amino acid-long class III Nicotinamide adenine dinucleotide (NAD⁺)-dependent histone that acts as a circadian deacetylase. Here we present a detailed in-silico analysis to address comparative structure-function relationship and interaction pattern of SIRT1-NAD⁺/Zn⁺² and SIRT1^NAD+/Zn+2-acetylated histone H4 (H4^KAC16) complexes. MD-based ensemble analysis suggested an overall loss of helical content (21.144–17.230%) in H4^KAC16-bound SIRT1^NAD+/Zn+2 due to conformational readjustments of 32 residues, as compared to SIRT1^NAD+/Zn+2. Due to increased flexibility, SIRT1-specific SER275, SER442 and ARG466 residues involved in NAD⁺ association facilitated in the formation of a transient tunnel (17.77 Å) that was further elongated to 19.25 Å upon SIRT1^NAD+/Zn+2 binding to H4^KAC16. A close conformation of SIRT1^NAD+/Zn+2 was achieved due to binding of H4^KAC16 that results in the movement of helical module towards Zn⁺² binding module together with Rossmann fold at NAD⁺ binding region. Furthermore, a 2-fold increase (4.31–8.82 Å) in the measured inter-atomic distance between imidazole nitrogen of conserved HIS363 and NAD⁺-specific 2′-hydroxyl group of ribose ring was evident in SIRT1^NAD+/Zn+2-H4^KAC16 complex. At 90 ns time scale, the distance between C6A of adenine ring and C2N of nicotinamide ring was more extended (19.32 Å) in SIRT1^NAD+/Zn+2-H4^KAC16 as compared to SIRT1^NAD+/Zn+2 (11.54 Å). These data suggest that H4^KAC16 binding to SIRT1 may coordinate an unusual conformational readjustment of nicotinamide ring at site-b and reposition of HIS363 to facilitate SIRT1-dependent deacetylase activity. Taken together, our findings will help in understanding the precise structural changes occurring in response to SIRT1 deacetylase activity of core histone.

昼夜节律是昼夜24小时内所有过程都涉及的生物周期。Sirtuin 1（SIRT1）是一个747个氨基酸长的III类烟酰胺腺嘌呤二核苷酸（NAD ⁺）依赖性组蛋白，可作为昼夜节律的乙酰化酶。在这里，我们提出了详细的计算机模拟分析，以解决SIRT1-NAD ⁺ / Zn ⁺²和SIRT1 ^{NAD + / Zn + 2-}乙酰化组蛋白H4（H4 ^KAC16）配合物的比较结构-功能关系和相互作用模式。基于MD的整体分析表明，H4 ^KAC16结合的SIRT1 ^{NAD + / Zn + 2}的螺旋含量总体损失（21.144–17.230％）与SIRT1 ^{NAD + / Zn + 2}相比，由于32个残基的构象调整。由于增加的灵活性，NAD ⁺缔合涉及的SIRT1特异性SER275，SER442和ARG466残基促进了瞬态隧道（17.77Å）的形成，当SIRT1 ^{NAD + / Zn + 2}与H4 ^KAC16结合后，该隧道进一步延长至^19.25Å。由于H4 ^KAC16的结合导致SIRT1 ^{NAD + / Zn + 2}的紧密构象，导致螺旋模块向Zn ⁺²结合模块移动，并在NAD ⁺处发生Rossmann折叠。结合区。此外，在保守HIS363和NAD的咪唑氮之间所测量的原子间距离的2倍增加（4.31-8.82）⁺核糖环的特异性2'-羟基在SIRT1是明显的^{NAD + /锌+ 2} -H4 ^KAC16复合体。在90纳秒的时间尺度，腺嘌呤环的C6A和烟酰胺环的C2N之间的距离更SIRT1扩展（19.32埃）^{NAD + /锌+ 2} - H4 ^KAC16相比于SIRT1 ^{NAD + /锌+ 2}（11.54埃）。这些数据表明H4 ^KAC16绑定到SIRT1可能会协调烟酰胺酰胺环的b位异常构象重新调整和HIS363的重新定位，以促进SIRT1依赖性脱乙酰酶活性。综上所述，我们的发现将有助于理解响应核心组蛋白SIRT1脱乙酰基酶活性而发生的确切结构变化。