Department of Chemistry, Faculty of Science, Kasetsart University, 50 Phaholyothin Rd, Chatuchak, Bangkok 10900, Thailand.
J Mol Model. 2011 Apr;17(4):769-75. doi: 10.1007/s00894-010-0732-6. Epub 2010 Jun 12.
PcFK1 is a member of the cysteine knot inhibitor family that displays anti-malarial properties. The naturally occurring molecule is ∼ 40 amino acids in length and forms a highly constrained 3D structure due to the presence of 3 disulfide and multiple intra-molecular H-bonds. Recent experimental studies on PcFK1 wild-type and mutants, where the cystiene residues of each disulfide bond were mutated into serine residues, suggest that alterations to these structural constraints can give rise to sizeable differences in SAR. To better understand the relationship between the dynamic inhibitor 3D structure, biophysical and biological properties we have performed solution based molecular dynamics calculations over 150 ns using the CHARMM forcefield. We have analyzed the theoretical trajectory in a systematic way using principal components analysis, which allows us to identify the correlated nature of the protein loop, turn and sheet movements. We have identified the key molecular motions that give rise to the differing SAR which has helped to more precisely direct our ongoing SAR studies in this important therapeutic area.
PcFK1 是半胱氨酸结抑制剂家族的一员，具有抗疟特性。天然存在的分子约有 40 个氨基酸，由于存在 3 个二硫键和多个分子内氢键，形成了高度受限的 3D 结构。最近对 PcFK1 野生型和突变体的实验研究表明，每个二硫键的半胱氨酸残基突变为丝氨酸残基，这些结构约束的改变可能导致 SAR 产生显著差异。为了更好地理解动态抑制剂 3D 结构、生物物理和生物学特性之间的关系，我们使用 CHARMM 力场进行了超过 150ns 的基于溶液的分子动力学计算。我们使用主成分分析（PCA）系统地分析了理论轨迹，这使我们能够识别蛋白质环、转角和片层运动的相关性。我们已经确定了导致不同 SAR 的关键分子运动，这有助于更精确地指导我们在这一重要治疗领域的持续 SAR 研究。
