Restricted sidechain plasticity in the structures of native proteins and complexes

Area of Science:

• Biochemistry
• Structural Biology
• Computational Biology

Background:

• Modern protein design methods can generate models with energies comparable to native protein structures and interfaces.
• Comparing native structures with computationally designed, isoenergetic models offers insights into evolutionary selection pressures.
• Selection may favor factors beyond the native state's energy, influencing protein properties.

Purpose of the Study:

• To investigate the differences in sidechain constraints between native protein structures/interfaces and computationally designed, isoenergetic models.
• To understand the implications of these constraints for protein evolution and stability.

Main Methods:

• Utilized computational protein design methodologies to generate models.
• Compared computed binding energies and stabilities of native and designed structures/interfaces.
• Analyzed sidechain conformational flexibility and constraints in both native and designed systems.

Main Results:

• Native protein structures and interfaces exhibit significantly greater sidechain constraints compared to designed counterparts.
• This difference persists even when designed and native structures have equal computed binding energy or stability.
• Designed interfaces and structures show less constrained sidechains at equivalent energy levels.

Conclusions:

• The higher degree of sidechain constraint in native proteins suggests evolutionary selection against potentially deleterious non-native interactions.
• Factors beyond simple binding energy or stability, such as minimizing off-target interactions, play a crucial role in protein evolution.
• Protein design can achieve high energy but may not fully recapitulate the subtle evolutionary optimizations present in natural proteins.