Department of Chemistry and Biochemistry, California State University Long Beach, 1250 Bellflower Boulevard, Long Beach, California 90840, United States.
Laboratory of Computational Biology, National Institutes of Health, National Heart, Lung and Blood Institute, 12 South Drive, Rm 3053, Bethesda, Maryland 20892-5690, United States.
J Phys Chem B. 2024 Sep 19;128(37):8956-8965. doi: 10.1021/acs.jpcb.4c03835. Epub 2024 Sep 6.
Photoinduced vitamin D formation occurs 10-15-fold faster in phospholipid bilayers (PLB) than in isotropic solution. It has been hypothesized that amphipatic interactions of the PLB with the rotationally flexible previtamin D (Pre) stabilize its helical conformers, enhancing thermal intramolecular [1,7]-hydrogen transfer, forming vitamin D. To test this hypothesis, we carried out molecular dynamics (MD) simulations of Pre in a PLB composed of dipalmitoylphosphatidylcholine (DPPC). We designed a classical force field capable of accurately describing the equilibrium composition of Pre conformers. Using adaptive biasing force MD simulations, we determined the free energy of Pre conformers in isotropic environments (hexane and gas-phase) and in the anisotropic environment of a DPPC PLB. We find a total increase of 25.5% of the population of both helical conformers (+20.5% ++ and +5% --) in DPPC compared to hexane. In view of ab initio simulations, showing that hydrogen transfer occurs in both helical conformers, our study strongly suggests the validity of the initial hypothesis. Regarding the amphipatic interactions of Pre with the PLB, we find that, similar to cholesterol (Chol) and 7-dehydrocholesterol (7-DHC), Pre entertains hydrogen bonds mainly to the carbonyl groups of DPPC and, to a lesser extent, with phosphate oxygen atoms and rarely to water molecules at the interface. We further report order parameters of the Pre/DPPC system, which are slightly smaller than those for Chol/DPPC and 7-DHC/DPPC, but larger than for pure DPPC. This indicates a loss in membrane viscosity upon photochemical ring-opening of 7-DHC to form Pre.
光诱导维生素 D 的形成在磷脂双分子层（PLB）中的速度比各向同性溶液中快 10-15 倍。人们假设 PLB 与旋转灵活的前维生素 D（Pre）的两亲相互作用稳定其螺旋构象，增强热分子内[1,7]-氢转移，形成维生素 D。为了验证这一假设，我们对由二棕榈酰磷脂酰胆碱（DPPC）组成的 PLB 中的 Pre 进行了分子动力学（MD）模拟。我们设计了一个经典的力场，能够准确描述 Pre 构象的平衡组成。使用自适应偏置力 MD 模拟，我们确定了 Pre 在各向同性环境（己烷和气相）和 DPPC PLB 的各向异性环境中的自由能。我们发现，与己烷相比，DPPC 中两种螺旋构象的总体种群增加了 25.5%（+20.5%++和+5%--）。鉴于从头算模拟表明氢转移发生在两种螺旋构象中，我们的研究强烈表明初始假设的有效性。关于 Pre 与 PLB 的两亲相互作用，我们发现，与胆固醇（Chol）和 7-脱氢胆固醇（7-DHC）类似，Pre 主要与 DPPC 的羰基形成氢键，并且在较小程度上与磷酸氧原子形成氢键，很少与界面处的水分子形成氢键。我们进一步报告了 Pre/DPPC 系统的序参数，其略小于 Chol/DPPC 和 7-DHC/DPPC 的序参数，但大于纯 DPPC 的序参数。这表明 7-DHC 光化学开环形成 Pre 后，膜粘度降低。
