Sharma Rajendra, De Sancho David, Muñoz Victor
National Biotechnology Center, CSIC, Madrid 28049, Spain.
Phys Chem Chem Phys. 2017 Nov 1;19(42):28512-28516. doi: 10.1039/c7cp04748g.
Proteins that fold upon binding to their partners exhibit complex binding behavior such as induced-fit. But the connections between the folding mechanism and the binding mode remain unknown. Here we focus on the high affinity complex between the physiologically and marginally unstable, fast folder PSBD and the E1 subunit of pyruvate dehydrogenase. Using coarse-grained simulations we investigate the binding to E1 of a partially disordered PSBD under two folding scenarios: two-state and downhill. Our simulations show that induced-fit binding requires that PSBD folds-unfolds in the downhill folding regime. In contrast, a two-state folding PSBD must fold completely before it binds. The reason is that effective coupling between folding and binding involves partially folded conformations, which are only sufficiently populated under the downhill folding regime. Our results establish a direct mechanistic link between complex binding and downhill folding, supporting the idea that PSBD operates functionally as a conformational rheostat.
与伴侣结合时发生折叠的蛋白质表现出复杂的结合行为，如诱导契合。但折叠机制与结合模式之间的联系仍不清楚。在这里，我们聚焦于生理上略微不稳定的快速折叠蛋白PSBD与丙酮酸脱氢酶E1亚基之间的高亲和力复合物。使用粗粒度模拟，我们研究了在两种折叠情形下部分无序的PSBD与E1的结合：两态折叠和下坡折叠。我们的模拟表明，诱导契合结合要求PSBD在下坡折叠状态下进行折叠-解折叠。相比之下，两态折叠的PSBD必须在结合之前完全折叠。原因是折叠与结合之间的有效耦合涉及部分折叠的构象，而这些构象仅在下坡折叠状态下有足够数量。我们的结果在复合物结合与下坡折叠之间建立了直接的机制联系，支持了PSBD在功能上作为构象变阻器发挥作用的观点。
