*Summary:* To facilitate the study of protein folding, we have developed a web service for protein folding rate and folding type prediction as well as for the calculation of a variety of topological parameters of protein structure, which is freely available to the community.&#xd;&#xa;*Availability:* http://sdbi.sdut.edu.cn/FDserve

Bin-Guang Ma

Hong-Yu Zhang

Ling-Ling Chen

English

Nature Precedings

FDserver: a web service for protein folding research 
Bin-Guang Ma1,2,*, Ling-Ling Chen1 and Hong-Yu Zhang1,*
1 Shandong Provincial Research Center for Bioinformatic Engineering and Technique, Center for Advanced Study, 
Shandong University of Technology, Zibo 255049, P. R. China and 2 College of Chemistry and Chemical Engineering, 
Suzhou University, Suzhou 215006, P. R. China 
 
ABSTRACT 
Summary: To facilitate the study of protein folding, we have 
developed a web service for protein folding rate and folding type 
prediction as well as for the calculation of a variety of topological 
parameters of protein structure, which is freely available to the 
community. 
Availability: http://sdbi.sdut.edu.cn/FDserver 
Contact: bgMa@sdut.edu.cn 
1 INTRODUCTION  
Protein folding is the process that a protein transforms from its 
denatured state to its native state with specific biological function. 
Folding rate is a measure of how fast this transformation process is 
while folding type indicates the kinetic behavior of this process 
(Jackson, 1998; Fersht and Daggett, 2002). It has been observed 
that proteins have a wide range of folding rates from within 
microseconds to almost hours (Ivankov and Finkelstein, 2004). 
The folding behaviors are also not unique but can be roughly 
classified as two sorts: two-state folding and multi-state folding. 
Protein folding is one of the central research fields of molecular 
biology.  
To predict protein folding rate and folding type, many 
parameters have been proposed in the past decade. Till now, 
several web services have been established (Zhou and Zhou, 2002; 
Gromiha et al., 2006; Capriotti and Casadio, 2007). However, the 
sequence-based folding type prediction has not been implemented 
yet. In our previous works, we studied systematically the 
relationship between a protein’s folding rate/type and its 
sequence/structure determinants and proposed three predictors, CI, 
Cp and IFT for folding rate and folding type prediction, respectively 
(Ma et al., 2006; Ma et al., 2007). Jointly with a newly developed 
indicator of protein folding rate IRT, the present work will 
implement a sequence-based predictor and a structure-based 
predictor for protein folding rate and folding type prediction. 
Moreover, the present work will also provide a calculator for 
protein topological parameters that stemmed from the protein 
folding research. This server is designed intentionally to facilitate 
protein folding and related research.  
2 DESCRIPTION OF FDSERVER 
FDserver comprises three components: (i) CIpred, a sequence-
based protein folding rate and folding type predictor; (ii) SBpred, a 
structure-based folding rate and folding type predictor; (iii) TPcalc, 
a calculator for the topological parameters of protein structure. The 
predictors are trained on a large dataset and the calculator can 
calculate nine topological parameters of protein structure. 
2.1 Training Data 
  
*To whom correspondence should be addressed.  
The training data are composed of 85 proteins, an ever largest 
dataset to our knowledge, 43 of which are two-state folders and the 
others are multi-state folders. Among these proteins, 62 natural 
ones with experimentally determined folding rates (Ivankov and 
Finkelstein, 2004) are used for training the folding rate predictors 
(Ma et al., 2006), while the totality are used for training the folding 
type predictors (for the detailed list of the proteins, see Ma et al., 
2007). The training data are also provided on the FDserver web 
site. 
2.2 CIpred: sequence-based folding rate and folding 
type predictor 
Based on the findings in our previous work, the sequence-based 
folding rate prediction is accomplished by using Composition 
Index (CI) (Ma et al., 2006). On the training dataset, the 
correlation coefficients (R) between CI and the folding rates of 
two-state folders, multi-state folders and their mixture are 0.73, 
0.70 and 0.73, respectively (jack-knife test), with average 
deviations all less than 1 unit (Ma et al., 2006). The folding type 
prediction is performed by using the predictor Cp which is defined 
based on the amino acid composition of a protein sequence (Ma et 
al., 2007). The folding type of a protein is indicated by the value of 
Cp, i.e., if Cp > 0, the folding type is predicted as multi-state; 
otherwise, two-state. On the training dataset, the accuracy (jack-
knife test) of the folding type prediction is 81% (Ma et al., 2007). 
2.3 SBpred: structure-based folding rate and folding 
type predictor 
A structure-based predictor called SBpred is also implemented 
which can predict the protein folding rate and folding type with 
relatively higher accuracy than that based only on sequence 
information. SBpred predicts protein folding type according to the 
value  of a folding type indicator IFT defined in our previous work 
(Ma et al., 2007), while it predicts folding rate according to a 
newly defined indicator IRT whose definition can be found on  the 
“Help” page of this server. On the training dataset, by using IFT, 
the prediction accuracy of folding type is 85% (jack-knife test) 
while by using IRT, the correlation coefficients (R) between IRT and 
the experimental folding rates are 0.80 for back-check and 0.76 for 
jack-knife test. See the “Help” page of this service for a detailed 
description. 
2.4 TPcalc: a calculator for topological parameters of 
protein structure 
TPcalc can calculate nine parameters that measure the topology of 
a protein structure. These parameters are collected from literature, 
including relative contact order (CO), absolute contact order 
(Abs_CO), chain topology parameter (CTP), total contact distance 
(TCD), long range order (LRO), fraction of local contacts (Flocal), 
long range contact order (LR_CO), clustering coefficient (CC) and 
absolute clustering coefficient (Abs_CC). The definition of these 
parameters and the corresponding publications can be found on the 
“Help” page of this service. For some parameters, thresholds exist 
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Ma et al. 
for the sequence separation (called Lcut) and/or distance definition 
(called Rcut) between two contacting residues. These thresholds are 
given the default values as reported in the corresponding original 
publications. It is also allowed for users to set these cut-off values 
on the server before calculation is performed.  
2.5 Implementation 
FDserver is built on a LAMP (Linux + Apache + MySQL + PHP) 
architecture and the web interface is shown in Figure 1. Through 
the home page (Fig. 1a), users can access the three components 
(Fig. 1b, 1c, 1d) of this server. For the calculation of topological 
parameters, users can submit a protein structure to TPcalc and 
select the parameters interested to perform calculation. For 
prediction of protein folding rate and/or folding type, if the protein 
structure information is available, SBpred can be employed. It 
accepts a protein structure as input and output the predicted folding 
rate and/or folding type. If only sequence information is available, 
a protein sequence can be submitted to the CIpred server, and then 
the folding type of the protein should be chosen to make a folding 
rate prediction; one may also make a folding type prediction at first 
when the folding type of the protein is unknown. The prediction 
results will be returned on a new web page. There is also an 
optional e-mail service on this server for delivering results. If an 
email address is provided, it will also receive the predicted or 
calculated results.  
 
Fig. 1. The web interface of FDserver. (a) The home page; (b) the CIpred 
page; (c) the SBpred page; (d) the TPcalc page. 
3 COMPARISON WITH AND LINKS TO OTHER 
SERVERS 
Compared with other servers, FDserver is currently the only one 
that can predict protein folding rate and folding type 
simultaneously directly from the primary sequence of a protein and 
the prediction accuracy is comparable to the other severs, which is 
particularly useful to new sequenced proteins that lack 3D 
structure information. Moreover, the present server provides a 
calculator for a variety of topological parameters which has never 
been served before. The present server also maintains links to the 
other servers and to the protein folding database (Fulton et al., 
2005). Therefore, it can be treated as a catalog for the resources of 
protein folding research and brings convenience to the users. 
4 LIMITATIONS AND POSSIBLE 
IMPROVEMENTS 
The present approach is a statistical approach and thus inevitably 
has dataset dependency as all the statistical approaches do. 
Although the training dataset used in this work is unprecedentedly 
large, the amount of the currently available data is still small 
considering the whole protein universe. In addition, the quality of 
the data is also not completely satisfying because of the discrepant 
experimental conditions of data acquisition. The appearance of the 
so-called “standard” set of experimental conditions for the kinetic 
study of protein folding may provide us with an ideal training 
dataset in the future (Maxwell et al., 2005).  
ACKNOWLEDGEMENTS 
This work was supported by the National Basic Research Program 
of China (2003CB114400) and the National Natural Science 
Foundation of China (30600119 and 30570383). 
 
 
 
REFERENCES 
Capriotti, E. and Casadio, R. (2007) K-Fold: a tool for the prediction of the protein 
folding kinetic order and rate. Bioinformatics, 23, 385-386. 
Fersht, A.R. and Daggett, V. (2002) Protein folding and unfolding at atomic resolution. 
Cell, 108, 573-582. 
Fulton, K.F., Devlin, G.L., Jodun, R.A., Silvestri, L., Bottomley, S.P., Fersht, A.R. 
and Buckle, A.M. (2005) PFD: a database for the investigation of protein folding 
kinetics and stability, Nucleic Acids Res., 33, D279-283. 
Gromiha,M.M. et al. (2006) FOLD-RATE: prediction of protein folding rates from 
amino acid sequence. Nucleic Acids Res, 34, W70-74. 
Ivankov, D.N. and Finkelstein, A.V. (2004) Prediction of protein folding rates from 
the amino acid sequence-predicted secondary structure. Proc. Natl. Acad. Sci. USA, 
101, 8942-8944. 
Jackson, S.E. (1998) How do small single-domain proteins fold? Fold Des, 3, R81-91. 
Ma, B.G. et al. (2006) Direct correlation between proteins' folding rates and their 
amino acid compositions: An ab initio folding rate prediction. Proteins, 65, 362-372. 
Ma, B.G. et al. (2007) What determines protein folding type? An investigation of 
intrinsic structural properties and its implications for understanding folding 
mechanisms. J. Mol. Biol. 370, 439-448. 
Maxwell, K.L. et al. (2005) Protein folding: Defining a "standard" set of experimental 
conditions and a preliminary kinetic data set of two-state proteins. Protein Sci, 14, 
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Zhou, H. and Zhou, Y. (2002) Folding rate prediction using total contact distance. 
Biophys J, 82, 458-463. 
 
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Direct correlation between proteins' folding rates and their amino acid compositions: An ab initio folding rate prediction.

FOLD-RATE: prediction of protein folding rates from amino acid sequence.

Folding rate prediction using total contact distance.

How do small single-domain proteins fold? Fold Des,

K-Fold: a tool for the prediction of the protein folding kinetic order and rate.

PFD: a database for the investigation of protein folding kinetics and stability,

Prediction of protein folding rates from the amino acid sequence-predicted secondary structure.

Protein folding and unfolding at atomic resolution.

Protein folding: Defining a &quot;standard&quot; set of experimental conditions and a preliminary kinetic data set of two-state proteins.

What determines protein folding type? An investigation of intrinsic structural properties and its implications for understanding folding mechanisms.

FDserver: A web service for protein folding research

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FDserver: A web service for protein folding research

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