Sartori Geraldo Rodrigues, Nascimento Alessandro S
São Carlos Institute of Physics, University of São Paulo, São Carlos, Brazil.
Front Mol Biosci. 2019 Jul 3;6:52. doi: 10.3389/fmolb.2019.00052. eCollection 2019.
The precise modeling of molecular interactions remains an important goal among molecular modeling techniques. Some of the challenges in the field include the precise definition of a Hamiltonian for biomolecular systems, together with precise parameters derived from Molecular Mechanics Force Fields, for example. The problem is even more challenging when interaction energies from different species are computed, such as the interaction energy involving a ligand and a protein, given that small differences must be computed from large energies. Here we evaluated the effects of the electrostatic model for ligand binding energy evaluation in the context of ligand docking. For this purpose, a classical Coulomb potential with distance-dependent dielectrics was compared with a Poisson-Boltzmann (PB) model for electrostatic potential computation, based on DelPhi calculations. We found that, although the electrostatic energies were highly correlated for the Coulomb and PB models, the ligand pose and the enrichment of actual ligands against decoy compounds, were improved when binding energies were computed using PB as compared to the Coulomb model. We observed that the electrostatic energies computed with the Coulomb model were, on average, ten times larger than the energies computed with the PB model, suggesting a strong overestimation of the polar interactions in the Coulomb model. We also found that a slightly smoothed Lennard-Jones potential combined with the PB model resulted in a good compromise between ligand sampling and energetic scoring.
分子相互作用的精确建模仍然是分子建模技术中的一个重要目标。该领域的一些挑战包括例如为生物分子系统精确定义哈密顿量，以及从分子力学力场导出精确参数。当计算来自不同物种的相互作用能时，问题更具挑战性，例如涉及配体和蛋白质的相互作用能，因为必须从大能量中计算出微小差异。在此，我们在配体对接的背景下评估了静电模型对配体结合能评估的影响。为此，基于DelPhi计算，将具有距离依赖性电介质的经典库仑势与用于静电势计算的泊松 - 玻尔兹曼（PB）模型进行了比较。我们发现，尽管库仑模型和PB模型的静电能高度相关，但与库仑模型相比，使用PB计算结合能时，配体构象以及实际配体相对于诱饵化合物的富集情况得到了改善。我们观察到，用库仑模型计算的静电能平均比用PB模型计算的能量大十倍，这表明库仑模型对极性相互作用有强烈的高估。我们还发现，将稍微平滑的 Lennard-Jones 势与PB模型相结合，在配体采样和能量评分之间达成了良好的折衷。
