l-DOPA-Containing Protein Autoxidation: An Empirical Valence Bond Simulation of the Rate-Limiting Step.

Parkinson's disease is a debilitating neurodegenerative disorder currently affecting ten million people worldwide. l-DOPA, or levodopa, is a crucial drug in addressing this issue, being a precursor of dopamine, a neurotransmitter which regulates motor functions, relieving the tremor symptom of Parkinson's. However, l-DOPA comes with side effects that are concerning for long-term treatment. Like dopamine, which can autoxidize to dopaquinone by entering a redox cycle, l-DOPA can also be converted to dopaquinone by the same mechanism, thus becoming a continuous source of hydrogen peroxide. Furthermore, because it is structurally similar to the amino acid tyrosine, it can also get incorporated into the proteins' sequence, thus becoming an additional source of oxidative stress for patients undergoing l-DOPA treatment. The rate-limiting step in the process of l-DOPA autoxidation is water protolysis, which yields hydroxide and hydronium ions. A similar rate-limiting step was observed in carbonic anhydrase II. In addition, the mechanism by which a hydroxide ion is transferred from bulk water was also considered. The next step, involving a nucleophilic attack by a hydroxide ion on a neutral amino group, along with cyclization, is not rate limiting. Using the Empirical Valence Bond (EVB) method, we computed the free-energy profiles for the reaction of l-DOPA incorporated into MAO A, replacing Tyr407. The calculated barrier of 33.93 kcal mol