Escape of a Small Molecule from Inside T4 Lysozyme by Multiple Pathways

Autor(es)

Nunes-Alves, Ariane ^[1] ; Zuckerman, Daniel M. ^[2] ; Arantes, Guilherme Menegon ^[1]

Afiliação do(s) autor(es)

^[1] Univ Sao Paulo, Inst Quim, Dept Biochem, Sao Paulo - Brazil

^[2] Oregon Hlth & Sci Univ, Sch Med, Dept Biomed Engn, Portland, OR 97201 - USA

• Tipo de documento: Artigo Científico
• Fonte: BIOPHYSICAL JOURNAL; v. 114, n. 5, p. 1058-1066, MAR 13 2018.
• Citações Web of Science: 11

Resumo

The T4 lysozyme L99A mutant is often used as a model system to study small-molecule binding to proteins, but pathways for ligand entry and exit from the buried binding site and the associated protein conformational changes have not been fully resolved. Here, molecular dynamics simulations were employed to model benzene exit from its binding cavity using the weighted ensemble (WE) approach to enhance sampling of low-probability unbinding trajectories. Independent WE simulations revealed four pathways for benzene exit, which correspond to transient tunnels spontaneously formed in previous simulations of apo T4 lysozyme. Thus, benzene unbinding occurs through multiple pathways partially created by intrinsic protein structural fluctuations. Motions of several a-helices and side chains were involved in ligand escape from metastable microstates. WE simulations also provided preliminary estimates of rate constants for each exit pathway. These results complement previous works and provide a semiquantitative characterization of pathway heterogeneity for binding of small molecules to proteins. (AU)

• Processo FAPESP: 14/17008-7 - Simulação computacional de fenômenos bioquímicos raros por métodos de aumento de amostragem
• Beneficiário: Ariane Ferreira Nunes Alves
• Linha de fomento: Bolsas no Brasil - Doutorado
• Processo FAPESP: 16/24096-5 - Simulação computacional de metaloenzimas e de proteínas flexíveis
• Beneficiário: Guilherme Menegon Arantes
• Linha de fomento: Auxílio à Pesquisa - Regular
• Processo FAPESP: 15/19912-5 - Simulação computacional de caminhos de saída de ligante pelo método de weighted ensemble
• Beneficiário: Ariane Ferreira Nunes Alves
• Linha de fomento: Bolsas no Exterior - Estágio de Pesquisa - Doutorado
• Processo FAPESP: 14/21900-2 - Desenvolvimento e aplicação de simulação computacional e análise espectroscópica para o estudo de metaloenzimas e de proteínas flexíveis
• Beneficiário: Guilherme Menegon Arantes
• Linha de fomento: Auxílio à Pesquisa - Regular