Fernández A
Instituto de Matemática (INMABB), Consejo Nacional de Investigaciones Científicas y Técnicas, Universidad Nacional del Sur, Avenida Alem 1253, Bahía Blanca 8000, Argentina.
Phys Rev E Stat Phys Plasmas Fluids Relat Interdiscip Topics. 1999 May;59(5 Pt B):5928-39. doi: 10.1103/physreve.59.5928.
The aim of this work is to provide a coarse codification of local conformational constraints associated with each folding motif of a peptide chain in order to obtain a rough solution to the protein folding problem. This is accomplished by implementing a discretized version of the soft-mode dynamics on a personal computer (PC). Our algorithm mimics a parallel process as it evaluates concurrent folding possibilities by pattern recognition. It may be implemented in a PC as a sequence of perturbation-translation-renormalization (p-t-r) cycles performed on a matrix of local topological constraints (LTM). This requires suitable representational tools and a periodic quenching of the dynamics required for renormalization. We introduce a description of the peptide chain based on a local discrete variable the values of which label the basins of attraction of the Ramachandran map for each residue. Thus, the local variable indicates the basin in which the torsional coordinates of each residue lie at a given time. In addition, a coding of local topological constraints associated with each secondary and tertiary structural motif is introduced. Our treatment enables us to adopt a computation time step of 81 ps, a value far larger than hydrodynamic drag time scales. Folding pathways are resolved as transitions between patterns of locally encoded structural signals that change within the 10 micros-100 ms time scale range. These coarse folding pathways are generated by the periodic search for structural patterns in the time-evolving LTM. Each pattern is recorded as a contact matrix, an operation subject to a renormalization feedback loop. The validity of our approach is tested vis-a-vis experimentally-probed folding pathways eventually generating tertiary interactions in proteins which recover their active structure under in vitro renaturation conditions. As an illustration, we focus on determining significant folding intermediates and late kinetic bottlenecks that occur within the first 10 ms of the bovine pancreatic trypsin inhibitor renaturation process. The probed cooperativity and nucleation effects, as well as diffusion-collision stabilization of secondary structure are shown to result from the persistence of relatively stable patterns through successive (p-t-r) cycles, thus acting as seeding patterns for further growth or hierarchical development.
这项工作的目的是对与肽链每个折叠基序相关的局部构象限制进行粗略编码，以便获得蛋白质折叠问题的近似解决方案。这是通过在个人计算机（PC）上实现软模式动力学的离散化版本来完成的。我们的算法模仿了一个并行过程，因为它通过模式识别评估并发的折叠可能性。它可以在PC上实现为对局部拓扑约束矩阵（LTM）执行的一系列微扰 - 平移 - 重整化（p - t - r）循环。这需要合适的表示工具以及重整化所需动力学的周期性猝灭。我们基于局部离散变量引入了肽链的描述，其值为每个残基的拉马钱德兰图的吸引盆进行标记。因此，局部变量指示每个残基的扭转坐标在给定时间所处的吸引盆。此外，还引入了与每个二级和三级结构基序相关的局部拓扑约束的编码。我们的处理方法使我们能够采用81皮秒的计算时间步长，该值远大于流体动力学阻力时间尺度。折叠途径被解析为在10微秒 - 100毫秒时间尺度范围内变化的局部编码结构信号模式之间的转变。这些粗略的折叠途径是通过在随时间演化的LTM中周期性地搜索结构模式而产生的。每个模式都记录为一个接触矩阵，该操作受到重整化反馈回路的影响。我们的方法的有效性通过与实验探测的折叠途径进行对比测试，最终在体外复性条件下产生三级相互作用并恢复其活性结构的蛋白质中得到验证。作为一个例子，我们专注于确定在牛胰蛋白酶抑制剂复性过程的前10毫秒内出现的重要折叠中间体和后期动力学瓶颈。所探测的协同性和成核效应，以及二级结构的扩散 - 碰撞稳定作用，被证明是由于相对稳定的模式在连续的（p - t - r）循环中持续存在，从而作为进一步生长或层次发展的种子模式。
