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Can one predict protein stability? An attempt to do so for residue 133 of T4 lysozyme using a combination of free energy derivatives, PROFEC, and free energy perturbation methods
Author(s) -
Wang Lu,
Veenstra David L.,
Radmer Randall J.,
Kollman Peter A.
Publication year - 1998
Publication title -
proteins: structure, function, and bioinformatics
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.699
H-Index - 191
eISSN - 1097-0134
pISSN - 0887-3585
DOI - 10.1002/(sici)1097-0134(19980901)32:4<438::aid-prot4>3.0.co;2-c
Subject(s) - lysozyme , chemistry , free energy perturbation , residue (chemistry) , perturbation (astronomy) , enzyme , stereochemistry , computational chemistry , crystallography , physics , organic chemistry , molecular dynamics , biochemistry , quantum mechanics
Free energy derivatives, pictorial representation of free energy changes (PROFEC) and free energy perturbation methods were employed to suggest the modifications that may improve the stability of a mutant T4 lysozyme with a S‐2‐amino‐3‐cyclopentylpropanoic acid residue (Cpe) at position 133. The free energy derivatives and PROFEC methods were used to locate promising sites where modifications may be introduced. The effects of several candidate modifications on the enzyme's stability were analyzed by the free energy perturbation method. We found that this scheme is able to effectively suggest modifications that may increase the enzyme's stability. The modifications investigated are the introduction of a methyl, a tert‐butyl or a trifluoromethyl group at the C ϵ2 position and a cyclopropyl group between the C δ2 and C ϵ2 position on the cyclopentyl ring. The stereochemistry of the introduced groups (in the α or β configurations) was studied. Our calculations predict that the introduction of a methyl group in the α configuration or a cyclopropyl group in the β configuration will increase the stability of the enzyme; the introduction of the two groups in the other configurations and the other modifications will decrease the stability of the enzyme. The results indicate that packing interactions can strongly influence the stability of the enzyme. Proteins 32:438–458, 1998. © 1998 Wiley‐Liss, Inc.