Modeling Protein Evolution - Computational Modeling of Biological Systems - page 313

2 The Challenges

Evolution involves a massively parallel operation occurring in large populations
over long periods of time. We seek ways to simulate this process in a reasonable
time with limited computational resources. This means we need to greatly speed
up and therefore grossly simplify the system. In order to model the evolution of
proteins, we need a model of how the proteins behave, a way of characterizing the
viability or fitness of a given protein, and a description of the population dynamics
of the evolutionary process. Developing simplified representations of these three
aspects has specific challenges.

1. Proteins are complex. Proteins can range from hundreds to thousands of amino
acids, representing thousands to tens of thousands of atoms. The number of
possible conformations exceeds the number of atoms in the universe by many
orders of magnitude. Proteins also interact intimately with their heterogeneous
environment, which can include water, ions, and complex bilayer membranes, as
well as other biomolecules such as nucleic acids and other proteins.
2. The interactions within proteins, and among proteins and their environments, are
not well understood. This is especially problematic given that the thermodynamic
properties of proteins often represent small differences between large numbers;
the large terms must be known to excruciatingly high accuracy in order for the
small differences to be meaningful.
3. Proteins have to fulfill multiple requirements, including the abilities to fold into
a stable, well-defined structure; maintain solubility; be trafficked to appropriate
parts of the cell (or excreted externally); and recognize, interact with, and
process other biological and environmental components. The specifics of these
constraints, and how they interact, are difficult to determine.
4. The structure and function of proteins can evolve, as well as the sequence. It is
difficult to predict how changing structural, functional, and sequence contexts
might alter subsequent evolutionary patterns.
5. In general, evolution involves competition between individuals with genomes
that encode multiple proteins. The evolutionary dynamics of a given gene variant
involves the fitness of those individuals that contain this variant, including how it
interacts with other genes and gene products as well as the environment. It is not
easy to quantify the complex and heterogeneous relationship between the fitness
of an individual and the properties of a single or few proteins encoded by their
genomes.
6. Evolution takes place in large, heterogeneous populations. The variation within
this population can have a strong effect on the evolutionary dynamics. The effect
of a mutation on an individual's fitness depends in part upon the characteristics
of other individuals in that population.

A range of different research approaches has been developed to address these
difficulties and complications.