Insights into All-Atom Protein Structure Prediction via in silico Simulations2013 Sigma Xi Student Research Showcase Daniel Wang

RESEARCH GOALS

To utilize in silico methods to perform de novo simulations of protein folding pathways and

predict the functional structures of proteins.

Proteins – Biological Workhorses

A map of 3200 protein interactions between 1700 proteins (Image from http://www.mdc-berlin.de/en/news/archive/2008/20080910-erwin_schr_dinger_prize_2008_goes_to_resea/index.html)

The central dogma of biology(Image from http://www.nyu.edu/

projects/vogel/Pics/centraldogma_2

BACKGROUND

Proteins serve a plethora of vital functions: growth and repair, cell-to-cell signaling, defense against pathogens, movement, catalyzing reactions

Protein function is determined by specific 3-dimensional structure

~130,000 binary protein-protein interactions in a human cell at any given time

Protein folding is the process of molecular self-assembly during which an extended chain of amino acids collapses to form a compact and specific three-dimensional structure

A protein becomes functional when it folds into a 3-dimensional structure.

Misfolded proteins can aggregate and lead to a range of diseases, such as Alzheimer’s and Parkinson’s

No current method exists to predict the functional structure of a protein from its amino acid sequence

Random Coil Structure

3-dimensional native structure

Protein Folding Problem

(Image from http://www.ks.uiuc.edu/villin-folding-process)

Folding Funnel Model Modern folding model =

energy of a protein with respect to systemic changes in geometry and is represented by funnel-shaped energy landscapes

Protein chain must negotiate multiple folding pathways with valley traps and mountain barriers

Conformational entropy that is lost during the folding process is compensated by an increase in free energy as the global minimum is approached

Thermodynamic protein folding funnel(Image from http://www.learner.org/courses/physics/visual/visual.html?shortname=funnel)

MD simulations calculate the physical movements of atoms in a system over a period of time, known as a trajectory.

Timesteps in the femtosecond (10-15 of a second) scale, MD simulations offer insight into intra- and inter-molecular interactions at an atomistic level

Molecular Dynamics Simulations

Implicit molecular dynamics environment (Image from http://www.yasara.org/benchmarks.htm)

Schematic of molecular dynamics steps

Replica Exchange MD

Allows for larger conformational searches by utilizing independent realizations of a system, known as replicas.

Each replica is coupled to a different thermostat temperature. Replicas are exchanged at regular time intervals, effectively allowing conformations to escape low temperature kinetic traps by “jumping” to alternate minima being sampled at higher temperatures

Schematic of replica exchange molecular dynamics

METHODOLOGY