Unravelling Constant pH Molecular Dynamics in Oligopeptides with Explicit Solvation Model

Area of Science:

• Biochemistry
• Computational Biology
• Molecular Dynamics

Background:

• Accurate simulation of protein conformational space and mechanisms requires precise amino acid protonation states.
• pH and electrochemical environments critically influence amino acid pKa values but are often overlooked in Molecular Dynamics (MD) simulations.
• Constant pH Molecular Dynamics (cpHMD) methods address this by incorporating effective pKa values for amino acids in complex structures.

Purpose of the Study:

• To assess the impact of explicit solvation on constant pH Molecular Dynamics (cpHMD) simulations of peptides.
• To investigate the influence of titratable amino acid positions within oligopeptides on simulation accuracy.
• To identify strategies for improving conformational sampling in cpHMD simulations.

Main Methods:

• Simulations of capped tripeptides with explicit solvation using a discrete cpHMD method in AMBER.
• Extended simulations to oligopeptides with varying positions of titratable amino acids.
• Analysis of conformational sampling and comparison with previous implicit solvent studies.

Main Results:

• Explicit solvation did not resolve previously identified weaknesses in cpHMD simulations.
• Separating titratable amino acids in oligopeptides can mitigate simulation limitations.
• The positioning of titratable residues significantly impacts conformational sampling efficiency.

Conclusions:

• Explicit solvation does not inherently improve conformational sampling in cpHMD simulations.
• Strategic placement of titratable amino acids offers a viable approach to enhance cpHMD simulation accuracy.
• Findings provide practical guidelines for optimizing cpHMD simulations in biochemical studies.