Epistatic interactions between residues in a proteindetermine its adaptability as well the shape of its evolutionary trajectory. While several studies have shown that strong selection pressures enrich epistatic interactions in an evolving protein, little is known about how epistatic interactions themselves change over time when selection pressures are not constant. Obtaining fitness data to measure epistasis in a protein over significant and evolutionarily relevant time scales is a daunting task, rendering a study of the long-term evolution of epistasis in a proteincurrently infeasible . Here we analyze the evolution of epistasis in the protease of the human immunodeficiency virus type 1 (HIV-1) using genomic sequences collected for almost a decade from  treated and untreated patients, to understand how proteins adapt to a changing environment of treatment over time. We show that mutual information between pairs of residues is a necessary (but not sufficient) condition for epistasis , allowing us to use information as a proxy for epistasis . We analyze the "fossils" of the evolutionary trajectories of a protein contained in the sequence data, and show that epistatic interactions continue to enrich in the HIV-1 protease as more potent drugs enter the market. While initially epistatic interactions are likely to constrain the evolvability of a protein, we find no evidence that the HIV-1 protease has reached its potential for adaptation after 9 years of adapting to a changing drug environment . The protein is able to encode information about novel and more potent drugs using epistatic interactions, while maintaining sufficient diversity and thermostability. We propose that this mechanism is central to protein evolution not just in HIV-1 protease, but for any protein adapting to rapidly changingconditions
Epistatic interactions between residues determine a protein's adaptability and shape its evolutionary trajectory. When a protein experiences a changed environment, it is under strong selection to find a peak in the new fitness landscape. It has been shown that strong selection increases epistatic interactions as well as the ruggedness of the fitness landscape, but little is known about how the epistatic interactions change under selection in the long-term evolution of a protein . Here we analyze the evolution of epistasis in the protease of the human immunodeficiency virus type 1 (HIV-1) using protease sequences collected for almost a decade from both treated and untreated patients, to understand how epistasis changes and how those changes impact the long-term evolvability of a protein. We use an information-theoretic proxy for epistasis that quantifies the co-variation between sites, and show that positive information is a necessary (but not sufficient) condition that detects epistasis in most cases . We analyze the "fossils" of the evolutionary trajectories of the protein contained in the sequence data, and show that epistasis continues to enrich under strong selection, but not for proteins whose environment is unchanged. The increase in epistasis compensates for the information loss due to sequence variability brought about by treatment, and facilitates adaptation in the increasingly rugged fitness landscape of treatment. While epistasis is thought to enhance evolvability via valley-crossing early-on in adaptation, it can hinder adaptation later when the landscape has turned rugged. However, we find no evidence that the HIV-1 protease has reached its potential for evolution after 9 years of adapting to a drug environment that itself is constantly changing.
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in a proteindetermine its adaptability as well the shape of
determine a protein's adaptability and shape
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While several studies have
When a protein experiences a changed environment, it is under strong selection to find a peak in the new fitness landscape. It has been
R
pressures enrich epistatic interactions in an evolving protein,
increases epistatic interactions as well as the ruggedness of the fitness landscape, but
R
epistatic interactions themselves change over time when selection pressures are not constant. Obtaining fitness data to measure epistasis in a protein over significant and evolutionarily relevant time scales is a daunting task, rendering a study of
the epistatic interactions change under selection in
R
epistasis in a proteincurrently infeasible
a protein
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genomic
protease
A
both
R
proteins adapt to a changing environment of treatment over time. We show that mutual information between pairs of residues
epistasis changes and how those changes impact the long-term evolvability of a protein. We use an information-theoretic proxy for epistasis that quantifies the co-variation between sites, and show that positive information
R
for epistasis , allowing us to use information as a proxy for epistasis
that detects epistasis in most cases
R
a
the
R
epistatic interactions continue to enrich in the HIV-1 protease as more potent drugs enter the market. While initially epistatic interactions are likely to constrain the evolvability of a protein,
epistasis continues to enrich under strong selection, but not for proteins whose environment is unchanged. The increase in epistasis compensates for the information loss due to sequence variability brought about by treatment, and facilitates adaptation in the increasingly rugged fitness landscape of treatment. While epistasis is thought to enhance evolvability via valley-crossing early-on in adaptation, it can hinder adaptation later when the landscape has turned rugged. However,
R
adaptation
evolution
R
changing drug environment . The protein is able to encode information about novel and more potent drugs using epistatic interactions, while maintaining sufficient diversity and thermostability. We propose that this mechanism is central to protein evolution not just in HIV-1 protease, but for any protein adapting to rapidly changingconditions
drug environment that itself is constantly changing.