Contribution of salt bridges toward protein thermostability

We present an extensive study of the structural factors suggested to be res ponsible for thermostability, in 18 nonredundant families of thermophilic a nd mesophilic proteins. Each of these 18 families consists of homologous th ermophile-mesophile pairs. with high resolution crystal structures for both pair-members available in the Protein Data Bank (PDB). We observe that bot h the thermophilic and the mesophilic proteins have similar hydrophobicitie s, oligomeric states, and hydrogen bonds. On the other hand, salt bridges i ncrease in most of the thermophilic proteins. Yet, on the other hand, salt bridges have been proposed to destabilize protein structures. Hence, here w e seek to understand why do salt bridges occur more frequently in thermophi lic proteins. Investigating this problem, we focus on the glutamate dehydro genase family. Computation of the electrostatic contribution of salt bridge energies by solving the Poisson equation in a continuum solvent medium, sh ows that the salt bridges in the glutamate dehydrogenase from the hyperther mophile Pyrococcus furiosus are highly stabilizing. In contrast. the salt b ridges in the mesophilic Clostridium symbiosum glutamate dehydrogenase cont ribute only marginally to protein stability. The presence of a larger numbe r of salt bridges cooperatively enhances their strength. Our results indica te that salt bridges and their networks may have an important role in rigid ifying the protein structure at high temperatures. Formation of salt bridge networks may help in explaining the increased occurrence and stability of salt bridges in hyperthermophiles.