An Indian butyrylcholinesterase variant L307P is not structurally stable: a molecular dynamics simulation study

Area of Science:

• Biochemistry
• Structural Biology
• Enzymology

Background:

• Human butyrylcholinesterase (BChE) activity is significantly reduced in the Indian Vysya community due to a specific L307P mutation.
• The structural basis for the negligible BChE activity in this silent variant remains unexplained.

Purpose of the Study:

• To investigate the structural stability of the Indian BChE L307P variant using molecular dynamics simulations.
• To compare the structural dynamics of the L307P variant with wild-type BChE and other known variants (D70G, E497V, V142M).

Main Methods:

• Molecular dynamics (MD) simulations were performed on wild-type and mutant BChE structures.
• Analysis included Cα root mean square deviation (RMSD) to assess conformational stability.
• Secondary structure stability and catalytic triad orientation were evaluated.

Main Results:

• The L307P Indian variant exhibited substantial conformational disturbance compared to wild-type BChE.
• Mutant proteins, particularly L307P, showed unstable secondary structures.
• Distortions in the catalytic triad and altered distances between key residues (His438, Glu325, Ser198) were observed, especially in L307P.

Conclusions:

• The negligible catalytic activity of the Indian BChE L307P variant is likely attributed to its inherent structural instability.
• Conformational changes and catalytic triad disruption underlie the functional deficiency of the L307P mutant.