What Is the Protonation State of Proteins in Crystals? Insights from Constant pH Molecular Dynamics Simulations

被引:0
|
作者
Aho, Noora [1 ,2 ,3 ,4 ]
Groenhof, Gerrit [1 ,2 ]
Buslaev, Pavel [1 ,2 ]
机构
[1] Univ Jyvaskyla, Nanosci Ctr, Jyvaskyla 40014, Finland
[2] Univ Jyvaskyla, Dept Chem, Jyvaskyla 40014, Finland
[3] Saarland Univ, Theoret Phys, D-66123 Saarbrucken, Germany
[4] Saarland Univ, Ctr Biophys, D-66123 Saarbrucken, Germany
基金
芬兰科学院;
关键词
PARTICLE MESH EWALD; EXPLICIT SOLVENT; RIBONUCLEASE-A; PK(A) VALUES; NEUTRON; CRYSTALLOGRAPHY; EVOLUTION; ENERGIES; COMPLEX;
D O I
10.1021/acs.jpcb.4c05947
中图分类号
O64 [物理化学(理论化学)、化学物理学];
学科分类号
070304 ; 081704 ;
摘要
X-ray crystallography is an important technique to determine the positions of atoms in a protein crystal. However, because the native environment in which proteins function, is not a crystal, but a solution, it is not a priori clear if the crystal structure represents the functional form of the protein. Because the protein structure and function often depend critically on the pH, the question arises whether proton affinities are affected by crystallization. X-ray diffraction usually does not reveal protons, which makes it difficult to experimentally measure pK a shifts in crystals. Here, we investigate whether this challenge can be addressed by performing in silico titration with constant pH molecular dynamics (MD) simulations. We compare the computed pK a values of proteins between solution and crystal environment and analyze these differences in the context of molecular interactions. For the proteins considered in this work, pK a shifts were mostly found for residues at the crystal interfaces, where the environment is more apolar in the crystal than in water. Although convergence was an obstacle, our simulations suggest that in principle it is possible to apply constant pH MD to protein crystals routinely and assess the effect of crystallization on protein function more systematically than with standard MD simulations. We also highlight technical challenges that need to be addressed to make MD simulations of crystals more reliable.
引用
收藏
页码:11124 / 11133
页数:10
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