Khalili Mey, Liwo Adam, Jagielska Anna, Scheraga Harold A
Baker Laboratory of Chemistry and Chemical Biology, Cornell University, Ithaca, New York 14853-1301, USA.
J Phys Chem B. 2005 Jul 21;109(28):13798-810. doi: 10.1021/jp058007w.
The implementation of molecular dynamics (MD) with our physics-based protein united-residue (UNRES) force field, described in the accompanying paper, was extended to Langevin dynamics. The equations of motion are integrated by using a simplified stochastic velocity Verlet algorithm. To compare the results to those with all-atom simulations with implicit solvent in which no explicit stochastic and friction forces are present, we alternatively introduced the Berendsen thermostat. Test simulations on the Ala(10) polypeptide demonstrated that the average kinetic energy is stable with about a 5 fs time step. To determine the correspondence between the UNRES time step and the time step of all-atom molecular dynamics, all-atom simulations with the AMBER 99 force field and explicit solvent and also with implicit solvent taken into account within the framework of the generalized Born/surface area (GBSA) model were carried out on the unblocked Ala(10) polypeptide. We found that the UNRES time scale is 4 times longer than that of all-atom MD simulations because the degrees of freedom corresponding to the fastest motions in UNRES are averaged out. When the reduction of the computational cost for evaluation of the UNRES energy function is also taken into account, UNRES (with hydration included implicitly in the side chain-side chain interaction potential) offers about at least a 4000-fold speed up of computations relative to all-atom simulations with explicit solvent and at least a 65-fold speed up relative to all-atom simulations with implicit solvent. To carry out an initial full-blown test of the UNRES/MD approach, we ran Berendsen-bath and Langevin dynamics simulations of the 46-residue B-domain of staphylococcal protein A. We were able to determine the folding temperature at which all trajectories converged to nativelike structures with both approaches. For comparison, we carried out ab initio folding simulations of this protein at the AMBER 99/GBSA level. The average CPU time for folding protein A by UNRES molecular dynamics was 30 min with a single Alpha processor, compared to about 152 h for all-atom simulations with implicit solvent. It can be concluded that the UNRES/MD approach will enable us to carry out microsecond and, possibly, millisecond simulations of protein folding and, consequently, of the folding process of proteins in real time.
我们在随附论文中描述的基于物理的蛋白质联合残基（UNRES）力场的分子动力学（MD）实现方法已扩展到朗之万动力学。运动方程通过使用简化的随机速度Verlet算法进行积分。为了将结果与无显式随机力和摩擦力的隐式溶剂全原子模拟结果进行比较，我们还引入了Berendsen恒温器。对Ala(10)多肽的测试模拟表明，在约5飞秒的时间步长下，平均动能是稳定的。为了确定UNRES时间步长与全原子分子动力学时间步长之间的对应关系，我们在未受阻的Ala(10)多肽上进行了采用AMBER 99力场和显式溶剂以及在广义Born/表面积（GBSA）模型框架内考虑隐式溶剂的全原子模拟。我们发现，UNRES时间尺度比全原子MD模拟的时间尺度长4倍，因为UNRES中对应最快运动的自由度被平均掉了。当还考虑到评估UNRES能量函数时计算成本的降低，UNRES（侧链 - 侧链相互作用势中隐含了水合作用）相对于显式溶剂全原子模拟至少能使计算速度提高4000倍，相对于隐式溶剂全原子模拟至少能提高65倍。为了对UNRES/MD方法进行初步的全面测试，我们对葡萄球菌蛋白A的46个残基B结构域进行了Berendsen热浴和朗之万动力学模拟。我们能够通过这两种方法确定所有轨迹都收敛到类似天然结构的折叠温度。作为比较，我们在AMBER 99/GBSA水平上对该蛋白进行了从头折叠模拟。使用单个Alpha处理器，通过UNRES分子动力学折叠蛋白A的平均CPU时间为30分钟，而隐式溶剂全原子模拟约为152小时。可以得出结论，UNRES/MD方法将使我们能够对蛋白质折叠进行微秒级甚至可能是毫秒级的模拟，从而实时模拟蛋白质的折叠过程。
