School of Engineering and Science, Jacobs University Bremen, Bremen D-28759, Germany.
Proteins. 2010 Oct;78(13):2809-19. doi: 10.1002/prot.22796.
Comparative or homology modeling of a target protein based on sequence similarity to a protein with known structure is widely used to provide structural models of proteins. Depending on the target-template similarity these model structures may contain regions of limited structural accuracy. In principle, molecular dynamics (MD) simulations can be used to refine protein model structures and also to model loop regions that connect structurally conserved regions but it is limited by the currently accessible simulation time scales. A recently developed biasing potential replica exchange (BP-REMD) method was used to refine loops and complete decoy protein structures at atomic resolution including explicit solvent. In standard REMD simulations several replicas of a system are run in parallel at different temperatures allowing exchanges at preset time intervals. In a BP-REMD simulation replicas are controlled by various levels of a biasing potential to reduce the energy barriers associated with peptide backbone dihedral transitions. The method requires much fewer replicas for efficient sampling compared with T-REMD. Application of the approach to several protein loops indicated improved conformational sampling of backbone dihedral angle of loop residues compared to conventional MD simulations. BP-REMD refinement simulations on several test cases starting from decoy structures deviating significantly from the native structure resulted in final structures in much closer agreement with experiment compared to conventional MD simulations.
基于与已知结构的蛋白质的序列相似性对目标蛋白质进行比较或同源建模，广泛用于提供蛋白质的结构模型。根据目标-模板的相似性，这些模型结构可能包含结构准确性有限的区域。原则上，分子动力学（MD）模拟可用于改进蛋白质模型结构，还可用于模拟连接结构保守区域的环区，但受到当前可访问的模拟时间尺度的限制。最近开发的偏置交换（BP-REMD）方法用于在原子分辨率下精细调整环区并完成诱饵蛋白结构，包括显式溶剂。在标准 REMD 模拟中，在不同温度下同时运行系统的多个副本，允许在预设时间间隔进行交换。在 BP-REMD 模拟中，副本由不同水平的偏置势控制，以降低与肽主链二面角转变相关的能量势垒。与 T-REMD 相比，该方法需要更少的副本即可实现有效的采样。该方法应用于几个蛋白质环，与传统的 MD 模拟相比，环残基的主链二面角构象采样得到了改善。从明显偏离天然结构的诱饵结构开始，对几个测试案例进行 BP-REMD 精修模拟，得到的最终结构与实验结果更为接近，而传统的 MD 模拟则更为接近。
