quantitative prediction of critical amino acid positions for protein folding

8/13/2019 Quantitative Prediction of Critical Amino Acid Positions for Protein Folding

1/13

AMIT


2/13

Main Feature

Prediction of protein's core residues by using ab initio prediction method/algorit

A new algorithm MIR2, is presented and validated on 3203 proteins from PDB wiaccuracy approaching 80%.

Structures are decomposed in Closed Loops, their limits constituting the observeresidues.


3/13

Introduction

Folding nucleus are defined as minimum set of amino acid residues necessary forformation of a stable protein core.

Traditionally, both thermodynamic and topological criteria have been used to defamino acid sequence regions.

a new property, common to almost all globular proteins is the Closed Loops or equTEFs (for Tightened-Ended-Fragments).

TEFs have two basic properties:

a) Their ends are located in the protein core andb) Their ends are close to each other in 3D space (C-distance smaller th

The length of TEFs varies typically from 10 to 50 residues.

The main point is that the TEF limits are in majority buried in the hydrophobic pand are presumably related to the folding nucleus.


4/13

Introduction

Experimental and theoretical analyses provide evidence that positioning of criticthe protein interior with parallel formation of loops (not necessarily in a stable sin the initial moments of folding.

Early Folding Residues (EFR, protected from solvent at times of the order of 1central role in the stability of the 3D structure.


5/13

Introduction

Proposed an ab initio algorithm, which simulates the early folding stages and outpof residues which have the highest propensity to be buried.

These residues, called MIRs, (for Most Interacting Residues), constitute about total number of residues.

Using the NCN (non-covalent neighbors) of the predicted residues, a new characthe Folding Profile (FP), is calculated.

The maxima of FP curve (MFPs, for Maxima of Folding Profile) constitute a seconof predicted critical positions, as their number is comparable to the observed TE

The obtained sets of MIR2 and MFP positions have been compared to the TEF lim10-25 residues limit) of the protein data set, assigned from their 3D structures

Using the 25-residue length cutoff in the TEF determination, the percentage of between predicted MFPs and observed TEF limits approached 80%.


6/13

Results

Results are presented in two steps:

1. the MIR2 analysis and comparisonwith TEFs is outlined for the case of yeastactin binding protein Abp1 SH3 domain,

2. Then, the results on the whole setof 3203 proteins are summarized andstatistically analyzed. The same analysis wascarried out by SCOP structural class as well,

for the 1788 proteins of the data set.


7/13

Results

The MIR2 simulation starts with thecalculation of the NCN curve, which leads tothe determination of the MIR2 positions.

In the case of yeast actin binding proteinAbp1 SH3 domain, there are eight residueswith NCN 6 (Fig. (1a)).

In a second stage, FP curve is obtained usingthe NCN curve. The maxima of FP curve (the

MFPs) constitute the second predictedposition set. Fig. (1b) shows the FP and theMFPs for 1JO8.


8/13

Results

The final step of the procedure is thecomparison between the predicted criticalpositions (MIR2s and MFPs) with the TEFlimits, calculated with both 25 and 50-residue maximal length cutoffs.

MFPs are found to be more accurate (whencompare to the experimental data).


9/13


10/13

Results

The comparison between the predicted andobserved critical positions is quantified bythe distribution of MIR2s and MFPs versustheir distance from the nearest TEF limit.

The histograms shown in Fig. (3) representthis distribution.

In both cases, the comparison of MIR2s andMFPs against the TEF limits presents a

major peak at the origin (zero distance). This is evidence that the residues predicted

to be MIR2s or MFPs statisticallycorrespond to TEF limits.


11/13

Results


12/13

Results


13/13

Conclusion

As a conclusion, one can reasonably postulate that the MIR2 algorithm is able to p

only the primary protein structure, particular positions that have two characterisburied in the core of the globules and they are mainly hydrophobic.

These positions are presumably present in the folding nucleus.

quantitative prediction of critical amino acid positions for protein folding

Documents