Including residual contact information into replica-exchange MD simulations significantly enriches native-like conformations

PloS One
Arthur VoroninAlexander Schug

Abstract

Proteins are complex biomolecules which perform critical tasks in living organisms. Knowledge of a protein's structure is essential for understanding its physiological function in detail. Despite the incredible progress in experimental techniques, protein structure determination is still expensive, time-consuming, and arduous. That is why computer simulations are often used to complement or interpret experimental data. Here, we explore how in silico protein structure determination based on replica-exchange molecular dynamics (REMD) can benefit from including contact information derived from theoretical and experimental sources, such as direct coupling analysis or NMR spectroscopy. To reflect the influence from erroneous and noisy data we probe how false-positive contacts influence the simulated ensemble. Specifically, we integrate varying numbers of randomly selected native and non-native contacts and explore how such a bias can guide simulations towards the native state. We investigate the number of contacts needed for a significant enrichment of native-like conformations and show the capabilities and limitations of this method. Adhering to a threshold of approximately 75% true-positive contacts within a simulation, we obtain ...Continue Reading

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Methods Mentioned

BETA
X-ray
NMR
protein folding

Software Mentioned

Cage
Trp
OPLS
CHARMM
GDT
CASP
AlphaFold
GROMACS
PyRosetta
AMBER

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