Interplay of Electrostatics and Hydrophobic Effects in the Metamorphic Protein Human Lymphotactin

Area of Science:

• Biochemistry
• Structural Biology
• Protein Dynamics

Background:

• Human lymphotactin (hLtn) exhibits two physiologically relevant native states: a monomer (hLtn10) at 10°C/200mM salt and a dimer (hLtn40) at 40°C/no salt.
• The conversion between these monomeric and dimeric states involves significant alterations in protein structure and interactions.

Purpose of the Study:

• To investigate the electrostatic and hydrophobic interactions governing the stability of hLtn monomer and dimer states.
• To elucidate the molecular mechanisms driving the conformational changes between hLtn10 and hLtn40.

Main Methods:

• Free energy perturbation calculations to assess the contribution of specific amino acid interactions (e.g., Arg 23-Arg 43) to protein stability.
• Analysis of changes in solvent accessible surface area for hydrophobic residues.
• Explicit and implicit solvent simulations to characterize conformational ensembles under varying solution conditions.

Main Results:

• Identified multiple like-charge pairs, beyond Arg 23-Arg 43, crucial for hLtn10 stability.
• hLtn40 demonstrates an increased number of salt bridges compared to hLtn10.
• Significant alterations in solvent accessible surface area for hydrophobic residues indicate their role in stabilizing the hLtn40 dimer.

Conclusions:

• Electrostatic and hydrophobic interactions play critical roles in modulating the relative stability of hLtn monomer and dimer forms.
• Understanding these interactions provides insights into protein conformational dynamics and allosteric regulation.
• Solvent simulation methods are valuable tools for characterizing protein behavior under different environmental conditions.