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Updated: Aug 14, 2026
07:08
Optimization of Synthetic Proteins: Identification of Interpositional Dependencies Indicating Structurally and/or Functionally Linked Residues
Published on: July 14, 2015
The Physicochemical Basis of Protein Evolution: Property-Informed Evolutionary Models (PRIME)
Hannah Kim1,2, Konrad Scheffler, Anton Nekrutenko3
1Institute for Genomics and Evolutionary Medicine, Temple University, Philadelphia, PA, USA.
Molecular Biology and Evolution
|August 12, 2026
Summary
We developed PRIME, a new model that uses protein physicochemical properties to understand evolution. PRIME accurately identifies biophysical constraints driving protein sequence and phylogenetic diversity.
Area of Science:
- Evolutionary biology
- Biophysics
- Computational biology
Background:
- Standard evolutionary models identify selection but not its biophysical basis.
- Protein evolution is shaped by complex interactions between sequence and biophysical properties.
Purpose of the Study:
- Introduce PRIME (PRoperty Informed Models of Evolution), a framework for codon-level maximum likelihood methods.
- Explicitly model amino acid exchangeability based on physicochemical properties.
- Resolve the biophysical basis of selective constraint across sequences and phylogenies.
Main Methods:
- Developed global (G-PRIME), episodic (E-PRIME), and site-specific (S-PRIME) implementations.
- Parameterized attributes like molecular volume, hydropathy, and secondary structure propensities.
- Analyzed 24 diverse datasets and 18,944 mammalian genes.
Main Results:
- PRIME significantly improves model fit by incorporating biophysical realism.
- Physicochemical constraints at individual sites are reliably detected in data-rich alignments (AUC = 0.91).
- E-PRIME reveals a hierarchy of constraints: core packing/beta-sheets are rigid, alpha-helix/electrostatics allow tuning.
Conclusions:
- PRIME transforms evolutionary rates into interpretable biophysical rules.
- Physicochemical properties are crucial for understanding protein evolution and diversity.
- PRIME aligns with deep learning representations and experimental fitness landscapes.
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The primary structure of a protein is its amino acid sequence.
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01:13Protein Organization
Overview
01:13Protein Organization
Overview