Anderson D G, Shirts R B, Cross T A, Busath D D
Zoology Department and Center for Neuroscience, Brigham Young University, Provo, Utah 84602, USA.
Biophys J. 2001 Sep;81(3):1255-64. doi: 10.1016/S0006-3495(01)75783-9.
Experimental and theoretical calculations indicate that the dipole moment of the four Trp side chains in gramicidin A (gA) channels modify channel conductance through long-range electrostatic interactions. Electrostatic ion/side-chain interaction energies along the channel were computed with CHARMM using ab initio atom charges for native and 4-, 5-, or 6-fluorinated Trp side chains. The bulk water reaction to the polar side chains was included using the method of images as implemented by, and channel waters in idealized structures were included. Ion/Trp interaction energies were approximately -0.6 kcal/mol throughout the channel for all four of the native Trp pairs. Channel waters produced a modest reduction in the magnitude of interactions, essentially offsetting images representing the bulk water outside the channel. The effects of side-chain fluorination depended on ring position and, to a lesser extent, residue number. Compared with native Trp, 5-fluorination reduces the translocation barrier with minor effects on the exit barrier. In contrast, 6-fluorination primarily reduces exit barrier. 4-Fluorination produces a more complex double-well energy profile. Effects of measured side-chain movements resulting from fluorination or change in lipid bilayer were negligible whereas thermal side chain librations cause large effects, especially in the region of the ion-binding sites.
实验和理论计算表明，短杆菌肽A（gA）通道中四个色氨酸侧链的偶极矩通过长程静电相互作用改变通道电导。使用CHARMM，利用从头算原子电荷计算了天然色氨酸侧链以及4-、5-或6-氟代色氨酸侧链沿通道的静电离子/侧链相互作用能。采用镜像法考虑了极性侧链对大量水的影响，同时包含了理想化结构中的通道水。对于所有四对天然色氨酸，整个通道内离子/色氨酸相互作用能约为-0.6千卡/摩尔。通道水使相互作用强度略有降低，基本上抵消了代表通道外大量水的镜像。侧链氟化的影响取决于环的位置，在较小程度上还取决于残基编号。与天然色氨酸相比，5-氟化降低了转运势垒，对出口势垒影响较小。相比之下，6-氟化主要降低出口势垒。4-氟化产生更复杂的双阱能量分布。由氟化或脂质双层变化引起的侧链运动测量值的影响可忽略不计，而热侧链摆动则产生较大影响，尤其是在离子结合位点区域。
